Difference between revisions of "General Information/Major Groups are Defined by the Type of Transposase They Use"

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'''<big>T</big>'''he principal factor in IS classification is the similarity, at the primary sequence level, of the enzymes which catalyze their movement, their transposases (Tpases). In addition, a variety of characteristics are also taken into account. These include: the length and sequence of the short imperfect terminal inverted repeat sequences (IRs) carried by many ISs at their ends (TIRs or ITRs in eukaryotes); the length and sequence of the short flanking direct target DNA repeats (DRs) (TSD, '''T'''arget '''S'''ite '''D'''uplication, in eukaryotes) often generated on insertion; the organization of their open reading frames or the target sequences into which they insert<ref>Chandler M, Mahillon J. Insertion Sequences Revisited. In: Craig NL, Lambowitz AM, Craigie R, Gellert M, editors. Mobile DNA II. American Society of Microbiology; 2002. p. 305–366. </ref><ref><nowiki><pubmed>9729608</pubmed></nowiki></ref><ref><nowiki><pubmed>24499397</pubmed></nowiki></ref><ref><nowiki><pubmed>26104715</pubmed></nowiki></ref>. IS and some transposons can also be divided into two major types based on the chemistry used in breaking and rejoining DNA during TE displacement: the DDE (and DEDD) and HUH enzymes. Additional types of transposase enzymes have been identified [[:Image:1.7.1.png|(Fig.7.1)]] but are generally associated with other types of transposon rather than IS.  
+
'''<big>T</big>'''he principal factor in IS classification is the similarity, at the primary sequence level, of the enzymes which catalyze their movement, their transposases (Tpases). In addition, a variety of characteristics are also taken into account. These include: the length and sequence of the short imperfect terminal inverted repeat sequences (IRs) carried by many ISs at their ends (TIRs or ITRs in eukaryotes); the length and sequence of the short flanking direct target DNA repeats (DRs) (TSD, '''T'''arget '''S'''ite '''D'''uplication, in eukaryotes) often generated on insertion; the organization of their open reading frames or the target sequences into which they insert<ref>Chandler M, Mahillon J. Insertion Sequences Revisited. In: Craig NL, Lambowitz AM, Craigie R, Gellert M, editors. Mobile DNA II. American Society of Microbiology; 2002. p. 305–366. </ref><ref><pubmed>9729608</pubmed></ref><ref><pubmed>24499397</pubmed></ref><ref><pubmed>26104715</pubmed></ref>. IS and some transposons can also be divided into two major types based on the chemistry used in breaking and rejoining DNA during TE displacement: the DDE (and DEDD) and HUH enzymes. Additional types of transposase enzymes have been identified [[:Image:1.7.1.png|(Fig.7.1)]] but are generally associated with other types of transposon rather than IS.  
  
 
A relatively new type of potential transposase, [[wikipedia:CRISPR#Cas_genes_and_CRISPR_subtypes|Cas1]], is associated with so-called casposons, elements that may resemble complex IS and are related to [[wikipedia:CRISPR|CRISPRs]] (for more details please see [https://tncentral.ncc.unesp.br/TnPedia/index.php/General_Information/The_casposases The Casposases] section).
 
A relatively new type of potential transposase, [[wikipedia:CRISPR#Cas_genes_and_CRISPR_subtypes|Cas1]], is associated with so-called casposons, elements that may resemble complex IS and are related to [[wikipedia:CRISPR|CRISPRs]] (for more details please see [https://tncentral.ncc.unesp.br/TnPedia/index.php/General_Information/The_casposases The Casposases] section).
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[[File:1.7.1.png|alt=|thumb|900x900px|border|'''Fig.7.1.''' Types of Transposon and catalytic sites. Each column shows a different type of transposase with the principal amino acids defining their catalytic sites shown at the top. Underneath are shown examples in which the atomic structures have been determined (May 2020) there is no overall structure of a bacterial Y2 enzyme from the IS91 family. Below the cartoons, the figure indicates some of the bacterial TE and, below, the eukaryotic TE which encode transposases with each of the catalytic centers. In boxes at the bottom are shown the nucleophiles used in each case to break the phosphodiester DNA bond. |center]]  
 
[[File:1.7.1.png|alt=|thumb|900x900px|border|'''Fig.7.1.''' Types of Transposon and catalytic sites. Each column shows a different type of transposase with the principal amino acids defining their catalytic sites shown at the top. Underneath are shown examples in which the atomic structures have been determined (May 2020) there is no overall structure of a bacterial Y2 enzyme from the IS91 family. Below the cartoons, the figure indicates some of the bacterial TE and, below, the eukaryotic TE which encode transposases with each of the catalytic centers. In boxes at the bottom are shown the nucleophiles used in each case to break the phosphodiester DNA bond. |center]]  
  
DDE enzymes, so-called because of a conserved Asp, Asp, Glu triad of amino acids which coordinate essential metal ions, use OH (e.g. H20) as a nucleophile in a transesterification reaction<ref name=":0"><pubmed>26104718</pubmed></nowiki></ref> [[:Image:1.7.1.png|(Fig.7.1)]] and [[:Image:1.8.1.png|(Fig.7.2)]]. IS with DDE enzymes are the most abundant type in the public databases [[:Image:1.4.2.png|(Fig.4.2)]]. This is partly due to the fact that the definition of an IS became implicitly coupled to the presence of a DDE Tpase, an idea probably reinforced by the similarity between Tpases of IS (and other TE) and the retroviral integrases [[:Image:1.8.1.png|(Fig.7.2)]]<ref><nowiki><pubmed>1963920</pubmed></nowiki></ref><ref><nowiki><pubmed>1850126</pubmed></nowiki></ref><ref><nowiki><pubmed>1314954</pubmed></nowiki></ref> particularly in the region including the catalytic site. More precisely, for these TE, the triad is DD(35)E in which the second D and E are separated by 35 residues. As more DDE transposases were identified, the distance separating the D and E residues was found to vary slightly ([[General Information/Major Groups are Defined by the Type of Transposase They Use#Transposases examined by secondary structure prediction programs|TABLE MGE transposases examined using secondary structure prediction programmes]])<ref name=":1"><pubmed>20067338</pubmed></nowiki></ref>. However, for certain IS, this distance was significantly larger. In these cases, the Tpases include an “insertion domain” between the second D and E residues <ref name=":1" /> with either α-helical or β-strand configurations [[:Image:1.8.3.png|(Fig.1.8.2)]]. Although in most cases this is a prediction, it has been confirmed by crystallographic studies for the IS''50'' [β-strand<ref><nowiki><pubmed>10207011</pubmed></nowiki></ref> and Hermes [α-helical;<ref><nowiki><pubmed>16041385</pubmed></nowiki></ref> Tpases. The function of these “insertion domains” is not entirely clear<ref name=":1" />. <center>
+
DDE enzymes, so-called because of a conserved Asp, Asp, Glu triad of amino acids which coordinate essential metal ions, use OH (e.g. H20) as a nucleophile in a transesterification reaction<ref name=":0"><pubmed>26104718</pubmed>
 +
 
 +
</ref> [[:Image:1.7.1.png|(Fig.7.1)]] and [[:Image:1.8.1.png|(Fig.7.2)]]. IS with DDE enzymes are the most abundant type in the public databases [[:Image:1.4.2.png|(Fig.4.2)]]. This is partly due to the fact that the definition of an IS became implicitly coupled to the presence of a DDE Tpase, an idea probably reinforced by the similarity between Tpases of IS (and other TE) and the retroviral integrases [[:Image:1.8.1.png|(Fig.7.2)]]<ref><pubmed>1963920</pubmed></ref><ref><pubmed>1850126</pubmed></ref><ref><pubmed>1314954</pubmed></ref> particularly in the region including the catalytic site. More precisely, for these TE, the triad is DD(35)E in which the second D and E are separated by 35 residues. As more DDE transposases were identified, the distance separating the D and E residues was found to vary slightly ([[General Information/Major Groups are Defined by the Type of Transposase They Use#Transposases examined by secondary structure prediction programs|TABLE MGE transposases examined using secondary structure prediction programmes]])<ref name=":1"><pubmed>20067338</pubmed>
 +
 
 +
</ref>. However, for certain IS, this distance was significantly larger. In these cases, the Tpases include an “insertion domain” between the second D and E residues <ref name=":1" /> with either α-helical or β-strand configurations [[:Image:1.8.3.png|(Fig.1.8.2)]]. Although in most cases this is a prediction, it has been confirmed by crystallographic studies for the [https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS50R IS''50''] [β-strand<ref><pubmed>10207011</pubmed></ref> and Hermes [α-helical;<ref><pubmed>16041385</pubmed></ref> Tpases. The function of these “insertion domains” is not entirely clear<ref name=":1" />. <center>
 
{|
 
{|
 
|[[Image:1.8.1.png|thumb|500x500px|'''Fig.7.2''' DDE transposase Glu-Glu-Asp domain.Top: variation in spacing of the amino acid DDE triad and the downstream conserved lysine or arginine residues. The references are one of the first realizations that there is a significant similarity between eukaryotic and prokaryotic transposases. Below: the original structure of the HIV integrase catalytic core domain showing the position of the 4 relevant amino acids (green arrows), a single divalent metal cation (blue circle), and the projected position of bound DNA. (Figure thanks to [https://www.niddk.nih.gov/about-niddk/staff-directory/biography/dyda-frederick F. Dyda]).  |alt=|border|none]]
 
|[[Image:1.8.1.png|thumb|500x500px|'''Fig.7.2''' DDE transposase Glu-Glu-Asp domain.Top: variation in spacing of the amino acid DDE triad and the downstream conserved lysine or arginine residues. The references are one of the first realizations that there is a significant similarity between eukaryotic and prokaryotic transposases. Below: the original structure of the HIV integrase catalytic core domain showing the position of the 4 relevant amino acids (green arrows), a single divalent metal cation (blue circle), and the projected position of bound DNA. (Figure thanks to [https://www.niddk.nih.gov/about-niddk/staff-directory/biography/dyda-frederick F. Dyda]).  |alt=|border|none]]
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! scope="col" |Family||Element (or protein) analyzed||Active or # copies in genome<sup>1</sup>||From secondary structure, type of DDE/D motif<sup>2</sup>||Relevant references<sup>3</sup>
 
! scope="col" |Family||Element (or protein) analyzed||Active or # copies in genome<sup>1</sup>||From secondary structure, type of DDE/D motif<sup>2</sup>||Relevant references<sup>3</sup>
 
|-
 
|-
| rowspan="2" |IS<i>1</i>
+
| rowspan="2" |[[IS Families/IS1 family|IS<i>1</i>]]
|IS<i>1N</i>||>40*||DD(24)E|| rowspan="2" |*Nyman et al., 1981; Ohta et al., 2002, 2004; Siguier et al., 2009
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS1N IS<i>1N</i>]||>40*||DD(24)E|| rowspan="2" |*Nyman et al., 1981; Ohta et al., 2002, 2004; Siguier et al., 2009
 
|-
 
|-
|IS<i>Sto9</i>||5||DD(20)E
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISSto9 IS<i>Sto9</i>]||5||DD(20)E
 
|-
 
|-
| rowspan="8" |IS<i>1595</i>
+
| rowspan="8" |[[IS Families/IS1595 family|IS<i>1595</i>]]
|IS<i>Pna2</i>||—||DD(36)N
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISPna2 IS<i>Pna2</i>]||—||DD(36)N
 
| rowspan="7" |Siguier et al., 2009
 
| rowspan="7" |Siguier et al., 2009
 
|-
 
|-
|IS<i>H4</i>||—||DD(36)E
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISH4 IS<i>H4</i>]||—||DD(36)E
 
|-
 
|-
|IS<i>1016C</i>||—||DD(34)E
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS1016C IS<i>1016C</i>]||—||DD(34)E
 
|-
 
|-
|IS<i>1595</i>||—||DD(35)N
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS1595 IS<i>1595</i>]||—||DD(35)N
 
|-
 
|-
|IS<i>Sod11</i>||13||DD(34)H
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISSod11 IS<i>Sod11</i>]||13||DD(34)H
 
|-
 
|-
|IS<i>NWi1</i>||—||DD(35)E
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISNWi1 IS<i>NWi1</i>]||—||DD(35)E
 
|-
 
|-
|IS<i>Nha5</i>||—||DD(33)E
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISNha5 IS<i>Nha5</i>]||—||DD(33)E
 
|-
 
|-
 
|<i>Merlin</i>: <i>MERLIN1_SM</i>||consensus||DD(36)E||Feschotte, 2004
 
|<i>Merlin</i>: <i>MERLIN1_SM</i>||consensus||DD(36)E||Feschotte, 2004
 
|-
 
|-
|IS<i>3</i>||IS<i>911</i>||Active||DD(35)E||Polard and Chandler, 1995; Rousseau et al., 2002
+
|[[IS Families/IS3 family|IS<i>3</i>]]||[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS911 IS<i>911</i>]||Active||DD(35)E||Polard and Chandler, 1995; Rousseau et al., 2002
 
|-
 
|-
|IS<i>481</i>||IS<i>481</i>||~100*||DD(35)E||*Glare et al., 1990; Chandler and Mahillon, 2002
+
|[[IS Families/IS481 family|IS<i>481</i>]]||[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS481 IS<i>481</i>]||~100*||DD(35)E||*Glare et al., 1990; Chandler and Mahillon, 2002
 
|-
 
|-
|IS<i>4</i>||IS<i>50R</i>||Active||PDB ID: 1muh||Rezsöhazy et al., 1993; Davies et al., 2000
+
|[[IS Families/IS4 and related families|IS<i>4</i>]]||[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS50R IS<i>50R</i>]||Active||PDB ID: 1muh||Rezsöhazy et al., 1993; Davies et al., 2000
 
|-
 
|-
| rowspan="2" |IS<i>701</i>
+
| rowspan="2" |[[IS Families/IS701 family|IS<i>701</i>]]
|IS<i>701</i>||Active (15*)|| rowspan="2" |DD(β-strand)E|| rowspan="2" |*Mazel et al., 1991
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS701 IS<i>701</i>]||Active (15*)|| rowspan="2" |DD(β-strand)E|| rowspan="2" |*Mazel et al., 1991
 
|-
 
|-
|IS<i>Rso17</i>||7
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISRso17 IS<i>Rso17</i>]||7
 
|-
 
|-
| rowspan="2" |IS<i>H3</i>
+
| rowspan="2" |[[IS Families/ISH3 family|IS<i>H3</i>]]
|IS<i>C1359</i>||5|| rowspan="2" |DD(β-strand)E|| rowspan="2" |—
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISC1359 IS<i>C1359</i>]||5|| rowspan="2" |DD(β-strand)E|| rowspan="2" |—
 
|-
 
|-
|IS<i>C1439A</i>||13
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISC1439A IS<i>C1439A</i>]||13
 
|-
 
|-
| rowspan="3" |IS<i>1634</i>
+
| rowspan="3" |[[IS Families/IS1634 family|IS<i>1634</i>]]
|IS<i>1634</i>||Active (~30*)|| rowspan="3" |DD(β-strand)E|| rowspan="3" |*Vilei et al., 1999
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS1634 IS<i>1634</i>]||Active (~30*)|| rowspan="3" |DD(β-strand)E|| rowspan="3" |*Vilei et al., 1999
 
|-
 
|-
|IS<i>Mac5</i>||7
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISMac5 IS<i>Mac5</i>]||7
 
|-
 
|-
|IS<i>Plu4</i>||7
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISPlu4 IS<i>Plu4</i>]||7
 
|-
 
|-
| rowspan="2" |IS<i>5</i>
+
| rowspan="2" |[[IS Families/IS5 and related IS1182 families|IS<i>5</i>]]
|IS<i>903</i>||Active||DD(65)E||Derbyshire et al., 1987; Rezsöhazy et al., 1993; Tavakoli et al., 1997
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS903 IS<i>903</i>]||Active||DD(65)E||Derbyshire et al., 1987; Rezsöhazy et al., 1993; Tavakoli et al., 1997
 
|-
 
|-
 
|PIF/Harbinger: PIFa (<i>Z. mays</i>)||Active||DD(59)E||Zhang et al., 2001; Kapitonov and Jurka, 2004; Sinzelle et al., 2008
 
|PIF/Harbinger: PIFa (<i>Z. mays</i>)||Active||DD(59)E||Zhang et al., 2001; Kapitonov and Jurka, 2004; Sinzelle et al., 2008
 
|-
 
|-
| rowspan="2" |IS<i>1182</i>
+
| rowspan="2" |[[IS Families/IS5 and related IS1182 families|IS<i>1182</i>]]
|"IS660||3|| rowspan="2" |DD(β-strand)E|| rowspan="2" |Takami et al., 2001
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS660 IS''660'']||3|| rowspan="2" |DD(β-strand)E|| rowspan="2" |Takami et al., 2001
 
|-
 
|-
|ISPsy6||14
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISPsy6 IS''Psy6'']||14
 
|-
 
|-
|IS<i>6</i>||IS<i>6100</i>||Active||DD(34)E||Martin et al., 1990; Mahillon and Chandler, 1998
+
|[[IS Families/IS6 family|IS<i>6</i>]]||[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS6100 IS<i>6100</i>]||Active||DD(34)E||Martin et al., 1990; Mahillon and Chandler, 1998
 
|-
 
|-
|IS<i>21</i>||IS<i>21</i>||Active||DD(45)E||Mahillon and Chandler, 1998; Berger and Haas, 2001
+
|[[IS Families/IS21 family|IS<i>21</i>]]||[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS21 IS<i>21</i>]||Active||DD(45)E||Mahillon and Chandler, 1998; Berger and Haas, 2001
 
|-
 
|-
|IS<i>30</i>||IS<i>30</i>||Active||DD(33)E||Caspers et al., 1984; Mahillon and Chandler, 1998
+
|[[IS Families/IS30 family|IS<i>30</i>]]||[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS30 IS<i>30</i>]||Active||DD(33)E||Caspers et al., 1984; Mahillon and Chandler, 1998
 
|-
 
|-
| rowspan="3" |IS<i>66</i>
+
| rowspan="3" |[[IS Families/IS66 family|IS<i>66</i>]]
|IS679||Active|| rowspan="3" |DD(α-helical?)E|| rowspan="3" |Han et al., 2001
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS679 IS''679'']||Active|| rowspan="3" |DD(α-helical?)E|| rowspan="3" |Han et al., 2001
 
|-
 
|-
|IS<i>Psy5</i>||33
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISPsy5 IS<i>Psy5</i>]||33
 
|-
 
|-
|IS<i>Mac8</i>||3
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISMac8 IS<i>Mac8</i>]||3
 
|-
 
|-
| rowspan="2" |IS<i>110</i>
+
| rowspan="2" |[[IS Families/IS110 family|IS<i>110</i>]]
|IS<i>492</i>||Active|| rowspan="2" |DEDD|| rowspan="2" |Perkins-Balding et al., 1999; Buchner et al., 2005
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS492 IS<i>492</i>]||Active|| rowspan="2" |DEDD|| rowspan="2" |Perkins-Balding et al., 1999; Buchner et al., 2005
 
|-
 
|-
|IS<i>1111</i>||20
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS1111A IS<i>1111</i>]||20
 
|-
 
|-
| rowspan="2" |IS<i>256</i>
+
| rowspan="2" |[[IS Families/IS256 family|IS<i>256</i>]]
|IS<i>256</i>||Active|| rowspan="2" |DD(α-helical)E||Mahillon and Chandler, 1998; Prudhomme et al., 2002
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS256 IS<i>256</i>]||Active|| rowspan="2" |DD(α-helical)E||Mahillon and Chandler, 1998; Prudhomme et al., 2002
 
|-
 
|-
|<i>MuDr</i>/<i>Foldback</i< (<i>Mutator</i>)||Active||Eisen et al., 1994; Babu et al., 2006; Hua-Van and Capy, 2008
+
|<i>MuDr</i>/<i>Foldback (<i>Mutator</i>)||Active||Eisen et al., 1994; Babu et al., 2006; Hua-Van and Capy, 2008
 
|-
 
|-
| rowspan="3" |IS<i>630</i>
+
| rowspan="3" |[[IS Families/IS630 family|IS<i>630</i>]]
|IS<i>Y100</i>|| rowspan="2" |Active||DD(34)E||Doak et al., 1994; Feng and Colloms, 2007
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISTcSa IS<i>Y100</i>]|| rowspan="2" |Active||DD(34)E||Doak et al., 1994; Feng and Colloms, 2007
 
|-
 
|-
 
|Tc1/<i>mariner</i>: <i>Mos1</i> (<i>D. mauritiana</i>)||PDB ID: 2f7t||Plasterk et al., 1999; Richardson et al., 2006
 
|Tc1/<i>mariner</i>: <i>Mos1</i> (<i>D. mauritiana</i>)||PDB ID: 2f7t||Plasterk et al., 1999; Richardson et al., 2006
Line 107: Line 111:
 
|<i>Zator</i>: <i>Zator-1_HM</i>||36*||DD(43)E||*Bao et al., 2009
 
|<i>Zator</i>: <i>Zator-1_HM</i>||36*||DD(43)E||*Bao et al., 2009
 
|-
 
|-
|IS<i>982</i>||IS<i>Pfu3</i>||5||DD(47)E||Mahillon and Chandler, 1998
+
|[[IS Families/IS982 family|IS<i>982</i>]]||[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISPfu3 IS<i>Pfu3</i>]||5||DD(47)E||Mahillon and Chandler, 1998
 
|-
 
|-
| rowspan="2" |IS<i>1380</i>
+
| rowspan="2" |[[IS Families/IS1380 family|IS<i>1380</i>]]
|IS1380A||~100*||DD(β-strand)E||*Takemura et al., 1991; Chandler and Mahillon, 2002
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS1380A IS''1380A'']||~100*||DD(β-strand)E||*Takemura et al., 1991; Chandler and Mahillon, 2002
 
|-
 
|-
 
|<i>piggyBac</i> (<i>T. ni</i>)||Active||DD(β-strand)D||Cary et al., 1989; Sarkar et al., 2003; Mitra et al., 2008
 
|<i>piggyBac</i> (<i>T. ni</i>)||Active||DD(β-strand)D||Cary et al., 1989; Sarkar et al., 2003; Mitra et al., 2008
 
|-
 
|-
|IS<i>As1</i>||IS<i>Azo3</i>||7||DD(β-strand)E/D?||—
+
|[[IS Families/ISAs1 family|IS<i>As1</i>]]||[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISAzo3 IS<i>Azo3</i>]||7||DD(β-strand)E/D?||—
 
|-
 
|-
| rowspan="2" |IS<i>L3</i>
+
| rowspan="2" |[[IS Families/ISL3 family|IS<i>L3</i>]]
|IS<i>31831</i>||Active|| rowspan="2" |DD(α-helical)E|| rowspan="2" |Suzuki et al., 2006
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS31831 IS<i>31831</i>]||Active|| rowspan="2" |DD(α-helical)E|| rowspan="2" |Suzuki et al., 2006
 
|-
 
|-
|IS<i>651</i>||22
+
|[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS651 IS<i>651</i>]||22
 
|-
 
|-
|Tn<i>3</i>||Tn<i>3</i> (<i>E. coli</i>)||Active||DD(α-helical?)E, DD(α-helical)E insertion||Grindley, 2002
+
|[[Transposons families/Tn3 family|Tn<i>3</i>]]||[http://tncentral.ncc.unesp.br/cgi-bin/tn_report.pl?id=Tn3-V00613 Tn<i>3</i>] (<i>E. coli</i>)||Active||DD(α-helical?)E, DD(α-helical)E insertion||Grindley, 2002
 
|-
 
|-
 
|<i>hAT</i>||<i>Hermes</i>||Active||PDB ID: 2bw3||Warren et al., 1994; Rubin et al., 2001; Hickman et al., 2005
 
|<i>hAT</i>||<i>Hermes</i>||Active||PDB ID: 2bw3||Warren et al., 1994; Rubin et al., 2001; Hickman et al., 2005
Line 130: Line 134:
 
|-
 
|-
 
| rowspan="2" |<i>Transib</i>
 
| rowspan="2" |<i>Transib</i>
|<i>>Transib1_AG</i>||Consensus|| rowspan="2" |DD(α-helical)E||Kapitonov and Jurka, 2005; Chen and Li, 2008
+
|<i>Transib1_AG</i>||Consensus|| rowspan="2" |DD(α-helical)E||Kapitonov and Jurka, 2005; Chen and Li, 2008
 
|-
 
|-
 
|<i>RAG1</i> (<i>M. musculus</i>)||Active||Kim et al., 1999; Landree et al., 1999; Lu et al., 2006
 
|<i>RAG1</i> (<i>M. musculus</i>)||Active||Kim et al., 1999; Landree et al., 1999; Lu et al., 2006
Line 139: Line 143:
  
 
==Major DDE transposition pathways==
 
==Major DDE transposition pathways==
Although DDE-type transposons share basic transposition chemistry, different TE vary in the steps leading to the formation of a unique insertion intermediate [[:Image:1.8.2.png|(Fig.7.4)]]<ref name=":0" /><ref name=":1" />. They catalyze the cleavage of a single DNA strand to generate a 3’OH at the TE ends which is subsequently used as a nucleophile to attack the DNA target phosphate backbone. This is known as the transferred strand. The variations are due to the way in which the second (non-transferred) strand is processed<ref name=":0" /><ref><nowiki><pubmed>10838584</pubmed></nowiki></ref><ref><nowiki><pubmed>14682279</pubmed></nowiki></ref>.  
+
Although DDE-type transposons share basic transposition chemistry, different TE vary in the steps leading to the formation of a unique insertion intermediate [[:Image:1.8.2.png|(Fig.7.4)]]<ref name=":0" /><ref name=":1" />. They catalyze the cleavage of a single DNA strand to generate a 3’OH at the TE ends which is subsequently used as a nucleophile to attack the DNA target phosphate backbone. This is known as the transferred strand. The variations are due to the way in which the second (non-transferred) strand is processed<ref name=":0" /><ref><pubmed>10838584</pubmed></ref><ref><pubmed>14682279</pubmed></ref>.  
  
There are several ways in which second-strand processing can occur [[:Image:1.8.2.png|(Fig.7.4)]]: for certain IS, the second strand is not cleaved but replication following the transfer of the first strand fuses donor and target molecules to generate cointegrates with a directly repeated copy at each donor/target junction. This is known as replicative transposition (e.g. IS''6,'' Tn''3'') or more precisely, '''T'''arget '''P'''rimed '''R'''eplicative '''T'''ransposition (TPRT) [[:Image:1.8.2.png|(Fig.7.4 pathway a)]].
+
There are several ways in which second-strand processing can occur [[:Image:1.8.2.png|(Fig.7.4)]]: for certain IS, the second strand is not cleaved but replication following the transfer of the first strand fuses donor and target molecules to generate cointegrates with a directly repeated copy at each donor/target junction. This is known as replicative transposition (e.g. [[IS Families/IS6 family|IS''6'']] and [[Transposons families/Tn3 family|Tn''3'']] families) or, more precisely, '''T'''arget '''P'''rimed '''R'''eplicative '''T'''ransposition (TPRT) [[:Image:1.8.2.png|(Fig.7.4 pathway a).]]
  
In the other pathways, the flanking donor DNA can be shed in several different ways: the non-transferred strand may be cleaved initially several bases within the IS prior to cleavage of the transferred strand [e.g. IS630 and Tc1<ref><nowiki><pubmed>8556864</pubmed></nowiki></ref><ref><nowiki><pubmed>7954797</pubmed></nowiki></ref><ref><nowiki><pubmed>17680987</pubmed></nowiki></ref> [[:Image:1.8.2.png|(Fig.7.4 pathway d)]]; the 3’OH generated by the first-strand cleavage may be used to attack the second strand to form a hairpin structure at the IS ends liberating the IS from flanking DNA and subsequently hydrolyzed to regenerate the 3’OH known as conservative or cut-and-paste transposition (e.g. [[IS Families/IS4 and related families|IS''4'' family]];<ref><nowiki><pubmed>26104553</pubmed></nowiki></ref> [[:Image:1.8.2.png|(Fig.7.4 pathway f)]] and [[:File:IS10.mp4|(Tn''10'' movie - see below)]] (Figs. [[:File:IS4.5.1.png|IS4.5]]; [[:File:IS4.6.png|IS4.6]]; [[:File:IS4.7.png|IS4.7]]); the 3’OH of the transferred strand from one IS end may attack the other to generate a donor molecule with a single strand bridge which is then replicated to produce a double-strand transposon circle intermediate and regenerating the original donor molecule known as copy-out-paste-in or more precisely '''D'''onor '''P'''rimed '''R'''eplicative '''T'''ransposition (DPRT) (e.g. [[IS Families/IS3 family|IS''3'' family]]) <ref><nowiki><pubmed>26350305</pubmed></nowiki></ref> [[:Image:1.8.2.png|(Fig.7.3 pathway e)]] and [[:Image:IS91-fast.mp4|(IS''911'' movie - see below)]]; or the 3’OH at the flank of the non-transferred strand may attack the second strand to form a hairpin on the flanking DNA and a 3’OH on the transferred strand (at present this has only been demonstrated for eukaryotic TE of the [[wikipedia:HAT_transposon|hAT family]] and in [[wikipedia:Transposable_element#Evolution|V(D)J recombination]] <ref><nowiki><pubmed>15616554</pubmed></nowiki></ref>) [[:Image:1.8.2.png|(Fig.7.4 pathway g)]].
+
In the other pathways, the flanking donor DNA can be shed in several different ways: the non-transferred strand may be cleaved initially several bases within the IS prior to cleavage of the transferred strand [e.g. [https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS630 IS''630''] and Tc1<ref><pubmed>8556864</pubmed></ref><ref><pubmed>7954797</pubmed></ref><ref><pubmed>17680987</pubmed></ref> [[:Image:1.8.2.png|(Fig.7.4 pathway d)]]; the 3’OH generated by the first-strand cleavage may be used to attack the second strand to form a hairpin structure at the IS ends liberating the IS from flanking DNA and subsequently hydrolyzed to regenerate the 3’OH known as conservative or cut-and-paste transposition (e.g. [[IS Families/IS4 and related families|IS''4'' family]];<ref><pubmed>26104553</pubmed></ref> [[:Image:1.8.2.png|(Fig.7.4 pathway f)]] and [[:File:IS10.mp4|(Tn''10'' movie - see below)]] (Figs. [[:File:IS4.5.1.png|IS4.5]]; [[:File:IS4.6.png|IS4.6]]; [[:File:IS4.7.png|IS4.7]]); the 3’OH of the transferred strand from one IS end may attack the other to generate a donor molecule with a single strand bridge which is then replicated to produce a double-strand transposon circle intermediate and regenerating the original donor molecule known as copy-out-paste-in or more precisely '''D'''onor '''P'''rimed '''R'''eplicative '''T'''ransposition (DPRT) (e.g. [[IS Families/IS3 family|IS''3'' family]]) <ref><pubmed>26350305</pubmed></ref> [[:Image:1.8.2.png|(Fig.7.3 pathway e)]] and [[:Image:IS91-fast.mp4|(IS''911'' movie - see below)]]; or the 3’OH at the flank of the non-transferred strand may attack the second strand to form a hairpin on the flanking DNA and a 3’OH on the transferred strand (at present this has only been demonstrated for eukaryotic TE of the [[wikipedia:HAT_transposon|hAT family]] and in [[wikipedia:Transposable_element#Evolution|V(D)J recombination]] <ref><pubmed>15616554</pubmed></ref>) [[:Image:1.8.2.png|(Fig.7.4 pathway g)]].
  
Clearly, many families produce double-strand circular intermediates but this does not necessarily mean that they all use the copy-paste DPRT mechanism since a circle could formally be generated by excision involving recombination of both strands<ref name=":0" />. These differences are reflected in the different IS families.  
+
Clearly, many families produce double-strand circular intermediates, but this does not necessarily mean that they all use the copy-paste DPRT mechanism, since a circle could formally be generated by excision involving recombination of both strands<ref name=":0" />. These differences are reflected in the different IS families.  
[[Image:1.8.2.png|thumb|820x820px|'''Fig.7.4'''. Major DDE transposition pathways: Dealing with the second strand. The color code is as follows: transposon DNA (green); flanking donor DNA (blue); target phosphates destined to be removed from the final liberated transposon (filled blue circles with a white “P”); phosphates destined to remain as 5′ transposon ends (open blue circles); the preferred stereoisomer, Sp or Rp, where known, is indicated within the circles; liberated 3′OH groups involved in strand joining reactions (open red circles); 3′OH destined to be removed from the liberated transposon (filled red circles); H2O is the attacking nucleophile in the hydrolysis reactions. '''(a)''' The Mu and Tn''3'' cleavage reactions. Note that the preferred stereoisomer has been demonstrated only for Mu and not for Tn''3''.  
+
[[Image:1.8.2.png|thumb|820x820px|'''Fig.7.4'''. Major DDE transposition pathways: Dealing with the second strand. The color code is as follows: transposon DNA (green); flanking donor DNA (blue); target phosphates destined to be removed from the final liberated transposon (filled blue circles with a white “P”); phosphates destined to remain as 5′ transposon ends (open blue circles); the preferred stereoisomer, Sp or Rp, where known, is indicated within the circles; liberated 3′OH groups involved in strand joining reactions (open red circles); 3′OH destined to be removed from the liberated transposon (filled red circles); H2O is the attacking nucleophile in the hydrolysis reactions. '''(a)''' The Mu and [http://tncentral.ncc.unesp.br/cgi-bin/tn_report.pl?id=Tn3-V00613 Tn''3''] cleavage reactions. Note that the preferred stereo isomer has been demonstrated only for Mu and not for [http://tncentral.ncc.unesp.br/cgi-bin/tn_report.pl?id=Tn3-V00613 Tn''3''].  
  
'''(b)''' Tn''7'' cleavage reactions. Cleavage of the transferred strand (top of panel) is shown occurring prior to cleavage of the non-transferred strand (middle) leading to the liberation of the transposon from flanking donor DNA (bottom of panel), although this order of cleavage reactions has not been demonstrated experimentally. The two types of cleavage are catalyzed by different enzymes.  
+
'''(b)''' [http://tncentral.ncc.unesp.br/cgi-bin/tn_report.pl?id=Tn7-NC_002525 Tn''7''] cleavage reactions. Cleavage of the transferred strand (top of panel) is shown occurring prior to cleavage of the non-transferred strand (middle) leading to the liberation of the transposon from flanking donor DNA (bottom of panel), although this order of cleavage reactions has not been demonstrated experimentally. The two types of cleavage are catalyzed by different enzymes.  
  
 
'''(c)''' Retroviral “processing” reaction, equivalent to cleavage of the transferred strand. An initial transcription step from the integrated provirus is indicated. The RNA genome is then encapsidated with a second copy and undergoes reverse transcription following infection to generate the double-strand DNA integration intermediate. The intermediate is flanked by only short fragments of donor material and does not require second-strand processing for insertion.  
 
'''(c)''' Retroviral “processing” reaction, equivalent to cleavage of the transferred strand. An initial transcription step from the integrated provirus is indicated. The RNA genome is then encapsidated with a second copy and undergoes reverse transcription following infection to generate the double-strand DNA integration intermediate. The intermediate is flanked by only short fragments of donor material and does not require second-strand processing for insertion.  
  
'''(d)''' Transposition by the members of the IS''630'' family and the Tc1/Mariner superfamily is initiated by cleavage of the non-transferred strand (top of panel) at several bases within the transposon end (middle) leaving these bases attached to the liberated flanks following cleavage of the transferred strand (bottom).  
+
'''(d)''' Transposition by the members of the [[IS Families/IS630 family|IS''630'' family]] and the Tc1/Mariner superfamily is initiated by cleavage of the non-transferred strand (top of panel) at several bases within the transposon end (middle) leaving these bases attached to the liberated flanks following cleavage of the transferred strand (bottom).  
  
'''(e)''' For IS''911'', IS''2'', IS''3'', and other members of the IS''3'' family, single-end hydrolysis occurs (top). The liberated 3′OH then directs a strand transfer reaction to the same strand several bases 5′ to the other end of the element. This results in the formation of a single-strand circle which is then resolved into a transposon circle by replication from the free 3′OH (filled red circle). Single-strand hydrolysis at each 3′ end within the circle generates a linear transposon which can then undergo integration.  
+
'''(e)''' For [https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS911 IS''911''], [https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS2 IS''2''], [https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS3 IS''3''], and other members of the [[IS Families/IS3 family|IS''3'' family]], single-end hydrolysis occurs (top). The liberated 3′OH then directs a strand transfer reaction to the same strand, several bases 5′ to the other end of the element. This results in the formation of a single-strand circle, which is then resolved into a transposon circle by replication from the free 3′OH (filled red circle). Single-strand hydrolysis at each 3′ end within the circle generates a linear transposon which can then undergo integration.  
  
'''(f)''' The IS''4'' family and piggyBac have similar mechanisms. Following the initial nucleophilic attack on the Rp target phosphate, the liberated 3′OH attacks an Sp phosphate in a trans-strand transfer reaction to generate a hairpin intermediate, liberating the transposon from its flanking donor DNA and inverting the target phosphate to its Rp configuration. These then become the substrates for second hydrolysis. Note that the stereochemistry has been analyzed only in the case of Tn''10''.
+
'''(f)''' The [[IS Families/IS4 and related families|IS''4'' family]] and piggyBac have similar mechanisms. Following the initial nucleophilic attack on the Rp target phosphate, the liberated 3′OH attacks a Sp phosphate in a trans-strand transfer reaction to generate a hairpin intermediate, liberating the transposon from its flanking donor DNA and inverting the target phosphate to its Rp configuration. These then become the substrates for second hydrolysis. Note that the stereochemistry has been analyzed only in the case of [http://tncentral.ncc.unesp.br/cgi-bin/tn_report.pl?id=Tn10-AF162223 Tn''10''].
  
 
'''(g)''' Hermes and V(D)J transposition occurs by initial cleavage of the non-transferred strand (top). The liberated 3′OH on the donor flank then attacks the opposite strand (middle) to generate a hairpin structure on the donor flank (bottom). The stereochemistry has been analyzed for V(D)J only.  
 
'''(g)''' Hermes and V(D)J transposition occurs by initial cleavage of the non-transferred strand (top). The liberated 3′OH on the donor flank then attacks the opposite strand (middle) to generate a hairpin structure on the donor flank (bottom). The stereochemistry has been analyzed for V(D)J only.  
Line 162: Line 166:
 
Modified and reprinted from Turlan and Chandler (2000),|alt=|border|center]]<center>
 
Modified and reprinted from Turlan and Chandler (2000),|alt=|border|center]]<center>
 
{| class="wikitable"
 
{| class="wikitable"
|+'''IS''911'' and Tn''10'' transposition mechanisms'''
+
|+'''[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS911 IS''911''] and [http://tncentral.ncc.unesp.br/cgi-bin/tn_report.pl?id=Tn10-AF162223 Tn''10''] transposition mechanisms'''
![[File:IS91-fast.mp4|center|380x380px]]'''<small>IS''911''.</small><small>Copy out - Paste in  (column e in figure 8.3)</small>'''
+
![[File:IS91-fast.mp4|center|380x380px]]'''<small>[https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS911 IS''911''].</small> <small>Copy out - Paste in  (column e in figure 8.3)</small>'''
![[File:IS10.mp4|center|380x380px]]<small>Tn''10''.</small> '''<small>Cut and paste (column f in figure 8.3)</small>'''
+
![[File:IS10.mp4|center|380x380px]]<small>[http://tncentral.ncc.unesp.br/cgi-bin/tn_report.pl?id=Tn10-AF162223 Tn''10''].</small> '''<small>Cut and paste (column f in figure 8.3)</small>'''
 
|}
 
|}
 
</center>
 
</center>
  
 
==Groups with DEDD Transposases==
 
==Groups with DEDD Transposases==
A similar type of Tpase, known as a DEDD Tpase, is related to the Holiday junction resolvase, RuvC <ref><nowiki><pubmed>12897009</pubmed></nowiki></ref><ref><nowiki><pubmed>15866929</pubmed></nowiki></ref><ref><nowiki><pubmed>11169105</pubmed></nowiki></ref> but is at present limited to only a single known IS family (IS''110''). The organization of family members is quite different from that of the DDE ISs: they do not contain the typical terminal IRs of the DDE IS (although one subgroup, IS''1111'', carry sub-terminal IR) and do not generate flanking target DRs on insertion. This implies that their transposition occurs using a different mechanism to the DDE IS. It seems probable that an intermediate resembling a four-way [[wikipedia:Holliday_junction|Holliday junction]] is involved.
+
A similar type of Tpase, known as a DEDD Tpase, is related to the Holiday junction resolvase, [[wikipedia:RuvABC|RuvC]] <ref><pubmed>12897009</pubmed></ref><ref><pubmed>15866929</pubmed></ref><ref><pubmed>11169105</pubmed></ref> but is at present limited to only a single known IS family ([[IS Families/IS110 family|IS''110'']]). The organization of family members is quite different from that of the DDE ISs: they do not contain the typical terminal IRs of the DDE IS (although one subgroup, [https://tncentral.ncc.unesp.br/TnPedia/index.php/IS_Families/IS110_family IS''1111''], carry sub-terminal IR) and do not generate flanking target DRs on insertion. This implies that their transposition occurs using a different mechanism as the DDE IS. It seems probable that an intermediate resembling a four-way [[wikipedia:Holliday_junction|Holliday junction]] is involved.
 
Moreover, in contrast to the DDE transposases in which a DNA binding domain invariably precedes the catalytic domain, DEDD transposases appear to include a DNA binding domain downstream from the catalytic domain.
 
Moreover, in contrast to the DDE transposases in which a DNA binding domain invariably precedes the catalytic domain, DEDD transposases appear to include a DNA binding domain downstream from the catalytic domain.
  
Line 176: Line 180:
 
==Groups with HUH Enzymes==
 
==Groups with HUH Enzymes==
 
{|
 
{|
|TE encoding the second major type of Tpase, called HUH (named for the conserved active site amino acid residues H=Histidine and U=large hydrophobic residue )[[:Image:1.7.1.png|(Fig.7.1)]] and [[:Image:1.10.1.png|(Fig.7.5)]], has been identified more recently. HUH enzymes are widespread single-strand nucleases. They include Rep proteins involved in bacteriophage and plasmid rolling circle replication and relaxases or Mob proteins involved in conjugative plasmid transfer<ref name=":2"><pubmed>23832240</pubmed></nowiki></ref>. They are limited to two prokaryotic (IS91 and IS200/IS605; <ref name=":3"><pubmed>26350330</pubmed></nowiki></ref>) and one eukaryotic (helitron<ref><nowiki><pubmed>26350323</pubmed></nowiki></ref>) TE family.
+
|TE encoding the second major type of Tpase, called HUH (named for the conserved active site amino acid residues H=Histidine and U=large hydrophobic residue )[[:Image:1.7.1.png|(Fig.7.1)]] and [[:Image:1.10.1.png|(Fig.7.5)]], has been identified more recently. HUH enzymes are widespread single-strand nucleases. They include Rep proteins involved in bacteriophage and plasmid rolling circle replication and relaxases or Mob proteins involved in conjugative plasmid transfer<ref name=":2"><pubmed>23832240</pubmed>
As Tpases, they are involved in presumed rolling circle transposition and also in single-strand transposition (see <ref name=":3" /><ref name=":0" />). Not only is the transposition chemistry radically different to that of DDE group elements, since it involves DNA cleavage using a tyrosine residue and transient formation of a phospho-tyrosine bond, but the associated transposons have an entirely different organization and include sub-terminal secondary structures instead of IRs (see [[General Information/What Is an IS?#Characteristics of insertion sequence families|IS families]] <ref name=":3" />). Note that these Tpases are not related to the well-characterized tyrosine site-specific recombinases such as phage integrases.
+
 
 +
</ref>. They are limited to two prokaryotic ([[IS Families/IS91-ISCR families|IS''91'']] and [[IS Families/IS200-IS605 family|IS''200/IS605'']]; <ref name=":3"><pubmed>26350330</pubmed>
 +
 
 +
</ref>) and one eukaryotic (helitron<ref><pubmed>26350323</pubmed></ref>) TE family.
 +
As Tpases, they are involved in presumed '''rolling circle transposition''' and also in single-strand transposition (see <ref name=":3" /><ref name=":0" />). Not only is the transposition chemistry radically different to that of DDE group elements, since it involves DNA cleavage using a tyrosine residue and transient formation of a phospho-tyrosine bond, but the associated transposons have an entirely different organization and include sub-terminal secondary structures instead of IRs (see [[General Information/What Is an IS?#Characteristics of insertion sequence families|IS families]] <ref name=":3" />). Note that these Tpases are not related to the well-characterized tyrosine site-specific recombinases such as phage integrases.
  
There are two major HUH Tpase families: Y1 and Y2 enzymes [[:Image:1.7.1.png|(Fig.7.1)]](see <ref name=":2" />) depending on whether there is a single or two catalytic Y residues. One family includes IS''91''-family transposases<ref><nowiki><pubmed>6282809</pubmed></nowiki></ref><ref><nowiki><pubmed>19709290</pubmed></nowiki></ref>, the other includes IS''200''/IS''605'' transposases<ref><nowiki><pubmed>6315530</pubmed></nowiki></ref><ref><nowiki><pubmed>3009825</pubmed></nowiki></ref><ref><nowiki><pubmed>6313217</pubmed></nowiki></ref><ref><nowiki><pubmed>11807059</pubmed></nowiki></ref><ref><nowiki><pubmed>9631304</pubmed></nowiki></ref><ref><nowiki><pubmed>9858724</pubmed></nowiki></ref>. Although these enzymes use the same Y-mediated cleavage mechanism, IS''200''/IS''605'' family Y1 transposases and IS''91'' transposases appear to carry out the transposition process in quite different ways. Neither carries terminal IRs nor do they generate DRs on insertion. Members of these families transpose using an entirely different mechanism to IS with DDE transposases<ref><nowiki><pubmed>11136468</pubmed></nowiki></ref><ref><nowiki><pubmed>16163392</pubmed></nowiki></ref>. The members of the IS''91'' insertion sequence family<ref><nowiki><pubmed>1321417</pubmed></nowiki></ref><ref><nowiki><pubmed>1310503</pubmed></nowiki></ref>, are related to a newly defined group, the IS''CR''<ref><nowiki><pubmed>16760305</pubmed></nowiki></ref> (see “[[General Information/IS91 and ISCR|IS''91''-related IS''CRs'']]”) and with eukaryotic [[wikipedia:Helitron_(biology)|helitrons]] [[:Image:1.7.1.png|(Fig.7.1)]]<ref><nowiki><pubmed>17850916</pubmed></nowiki></ref>. These IS carry sub-terminal sequences which are able to form hairpin secondary structures [[:Image:1.3.2.png|(Fig.3.2)]]. This is particularly marked in the IS''200''/IS''605'' family elements and, at least in the case of this family, it is these structures that are recognized by the transposase<ref name=":3" />.
+
There are two major HUH Tpase families: Y1 and Y2 enzymes [[:Image:1.7.1.png|(Fig.7.1)]](see <ref name=":2" />) depending on whether there is a single or two catalytic Y residues. One family includes IS''91''-family transposases<ref><pubmed>6282809</pubmed></ref><ref><pubmed>19709290</pubmed></ref>, the other includes [[IS Families/IS200-IS605 family|IS''200''/IS''605'']] transposases<ref><pubmed>6315530</pubmed></ref><ref><pubmed>3009825</pubmed></ref><ref><pubmed>6313217</pubmed></ref><ref><pubmed>11807059</pubmed></ref><ref><pubmed>9631304</pubmed></ref><ref><pubmed>9858724</pubmed></ref>. Although these enzymes use the same Y-mediated cleavage mechanism, [[IS Families/IS200-IS605 family|IS''200''/IS''605'' family]] Y1 transposases and [[IS Families/IS91-ISCR families|IS''91'' transposases]] appear to carry out the transposition process in quite different ways. Neither carries terminal IRs nor do they generate DRs on insertion. Members of these families transpose using an entirely different mechanism to IS with DDE transposases<ref><pubmed>11136468</pubmed></ref><ref><pubmed>16163392</pubmed></ref>. The members of the [[IS Families/IS91-ISCR families|IS''91'']] insertion sequence family<ref><pubmed>1321417</pubmed></ref><ref><pubmed>1310503</pubmed></ref>, are related to a newly defined group, the IS''CR''<ref><pubmed>16760305</pubmed></ref> (see “[[General Information/IS91 and ISCR|IS''91''-related IS''CRs'']]”) and with eukaryotic [[wikipedia:Helitron_(biology)|helitrons]] [[:Image:1.7.1.png|(Fig.7.1)]]<ref><pubmed>17850916</pubmed></ref>. These IS carry sub-terminal sequences which are able to form hairpin secondary structures [[:Image:1.3.2.png|(Fig.3.2)]]. This is particularly marked in the [[IS Families/IS200-IS605 family|IS''200''/IS''605'' family]] elements and, at least in the case of this family, it is these structures that are recognized by the transposase<ref name=":3" />.
  
  
Line 201: Line 209:
 
<br />
 
<br />
  
|[[Image:1.10.1.png|thumb|600x600px|'''Fig.7.5.''' The HUH enzymes. Organization of representative HUH domain-containing  proteins is shown; they contain HUH, helicase, oligomerization (OD) and proposed Zn - binding (not necessarily structurally related) domains. The length of each protein is indicated in numbers of amino acids, and those proteins for which HUH domain structures are available are indicated with an asterisk; the HUH motif data are from [https://pubmed.ncbi.nlm.nih.gov/8374079/ Koonin & Ilyina Biosystems 30, 241–268 (1993)] (motif 2) and [https://pubmed.ncbi.nlm.nih.gov/19396961/ Garcillan-Barcia et al., FEMS Microbiol. Rev. 33, 657–687 (2009)] (motif III); the Y motif data are from [https://pubmed.ncbi.nlm.nih.gov/8374079/ Koonin & Ilyina  Biosystems 30, 241–268 (1993)] (motif 3) and [https://pubmed.ncbi.nlm.nih.gov/19396961/ Garcillan-Barcia, et al;,  FEMS Microbiol.  Rev. 33 , 657–687 (2009)] (motif I). The assigned domain organizations are taken from phage φ  X174 protein A (gpA) ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693155/ Boer et al. EMBO J. 28, 1666–1678 (2009)]),  AAV Rep78  ([https://jvi.asm.org/content/71/6/4461 Smith et al.,  J. Virol. 71, 4461–4471 (1997)]), tomato yellow leaf curl virus (TYLCV) Rep  ([https://www.pnas.org/content/99/16/10310 Campos-Olivas et al  Proc. Natl Acad. Sci. USA  99, 10310–10315 (2002)]) , plasmid pMV158  RepB  ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693155/ Boer et al. EMBO J. 28, 1666–1678  (2009)]), plasmid R388 TrwC  ([https://pubmed.ncbi.nlm.nih.gov/14625590/ Guasch et al. Nature Struct. Biol.10, 1002–1010 (2003)]), plasmid RSF1010 MobA (mobilization protein A)  ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894915/ Monzingo et al. J. Mol. Biol. 366, 165–178 (2007)]), transposases from the insertion sequences IS608 ([https://pubmed.ncbi.nlm.nih.gov/16209952 Ronning et al. Mol. Cell  20  , 143–154 (2005)]), IS91 and insertion sequence with a common region 1 (ISCR1) (S. Messing, A.B.H. and F.D., unpublished observations), and HeliBat1 (a consensus sequence from a bioinformatic prediction). |alt=|border|none]]
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|[[Image:1.10.1.png|thumb|600x600px|'''Fig.7.5.''' The HUH enzymes. Organization of representative HUH domain-containing  proteins is shown; they contain HUH, helicase, oligomerization (OD) and proposed Zn - binding (not necessarily structurally related) domains. The length of each protein is indicated in numbers of amino acids, and those proteins for which HUH domain structures are available are indicated with an asterisk; the HUH motif data are from [https://pubmed.ncbi.nlm.nih.gov/8374079/ Koonin & Ilyina Biosystems 30, 241–268 (1993)] (motif 2) and [https://pubmed.ncbi.nlm.nih.gov/19396961/ Garcillan-Barcia et al., FEMS Microbiol. Rev. 33, 657–687 (2009)] (motif III); the Y motif data are from [https://pubmed.ncbi.nlm.nih.gov/8374079/ Koonin & Ilyina  Biosystems 30, 241–268 (1993)] (motif 3) and [https://pubmed.ncbi.nlm.nih.gov/19396961/ Garcillan-Barcia, et al;,  FEMS Microbiol.  Rev. 33 , 657–687 (2009)] (motif I). The assigned domain organizations are taken from phage φ  X174 protein A (''gpA'') ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693155/ Boer et al. EMBO J. 28, 1666–1678 (2009)]),  AAV Rep78  ([https://jvi.asm.org/content/71/6/4461 Smith et al.,  J. Virol. 71, 4461–4471 (1997)]), tomato yellow leaf curl virus (TYLCV) Rep  ([https://www.pnas.org/content/99/16/10310 Campos-Olivas et al  Proc. Natl Acad. Sci. USA  99, 10310–10315 (2002)]) , plasmid pMV158  RepB  ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693155/ Boer et al. EMBO J. 28, 1666–1678  (2009)]), plasmid R388 TrwC  ([https://pubmed.ncbi.nlm.nih.gov/14625590/ Guasch et al. Nature Struct. Biol.10, 1002–1010 (2003)]), plasmid RSF1010 MobA (mobilization protein A)  ([https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1894915/ Monzingo et al. J. Mol. Biol. 366, 165–178 (2007)]), transposases from the insertion sequences [https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=ISHp608 IS''608''] ([https://pubmed.ncbi.nlm.nih.gov/16209952 Ronning et al. Mol. Cell  20  , 143–154 (2005)]), [https://tncentral.ncc.unesp.br/ISfinder/scripts/ficheIS.php?name=IS91 IS''91''] and insertion sequence with a common region 1 (IS''CR1'') (S. Messing, A.B.H. and F.D., unpublished observations), and HeliBat1 (a consensus sequence from a bioinformatic prediction). |alt=|border|none]]
 
|}
 
|}
  
 
==Groups with S-Transposases==
 
==Groups with S-Transposases==
  
The third transposase family is represented by IS''607'' which carries a Tpase closely related to serine recombinases such as the resolvases of Tn''3'' family elements. Little is known about their transposition mechanism. However, it appears likely, in view of the known activities of resolvases, that IS''607'' transposition may involve a double-strand DNA intermediate ([[wikipedia:Nigel_Grindley|Grindley]] cited as pers. comm. in <ref><nowiki><pubmed>17347521</pubmed></nowiki></ref>) see also <ref><nowiki><pubmed>24195768</pubmed></nowiki></ref> [[:Image:1.7.1.png|(Fig.7.1)]].  
+
The third transposase family is represented by [[IS Families/IS607 family|IS''607'']] which carries a Tpase closely related to serine recombinases such as the resolvases of [[Transposons families/Tn3 family|Tn''3'' family elements]]. Little is known about their transposition mechanism. However, it appears likely, in view of the known activities of resolvases, that [[IS Families/IS607 family|IS''607'']] transposition may involve a double-strand DNA intermediate ([[wikipedia:Nigel_Grindley|Grindley]] cited as pers. comm. in <ref><pubmed>17347521</pubmed></ref>) see also <ref><pubmed>24195768</pubmed></ref> [[:Image:1.7.1.png|(Fig.7.1)]].  
  
 
==Groups with Y-Transposases==
 
==Groups with Y-Transposases==

Latest revision as of 20:56, 9 August 2021

The principal factor in IS classification is the similarity, at the primary sequence level, of the enzymes which catalyze their movement, their transposases (Tpases). In addition, a variety of characteristics are also taken into account. These include: the length and sequence of the short imperfect terminal inverted repeat sequences (IRs) carried by many ISs at their ends (TIRs or ITRs in eukaryotes); the length and sequence of the short flanking direct target DNA repeats (DRs) (TSD, Target Site Duplication, in eukaryotes) often generated on insertion; the organization of their open reading frames or the target sequences into which they insert[1][2][3][4]. IS and some transposons can also be divided into two major types based on the chemistry used in breaking and rejoining DNA during TE displacement: the DDE (and DEDD) and HUH enzymes. Additional types of transposase enzymes have been identified (Fig.7.1) but are generally associated with other types of transposon rather than IS.

A relatively new type of potential transposase, Cas1, is associated with so-called casposons, elements that may resemble complex IS and are related to CRISPRs (for more details please see The Casposases section).

Groups with DDE Transposases

Fig.7.1. Types of Transposon and catalytic sites. Each column shows a different type of transposase with the principal amino acids defining their catalytic sites shown at the top. Underneath are shown examples in which the atomic structures have been determined (May 2020) there is no overall structure of a bacterial Y2 enzyme from the IS91 family. Below the cartoons, the figure indicates some of the bacterial TE and, below, the eukaryotic TE which encode transposases with each of the catalytic centers. In boxes at the bottom are shown the nucleophiles used in each case to break the phosphodiester DNA bond.

DDE enzymes, so-called because of a conserved Asp, Asp, Glu triad of amino acids which coordinate essential metal ions, use OH (e.g. H20) as a nucleophile in a transesterification reaction[5] (Fig.7.1) and (Fig.7.2). IS with DDE enzymes are the most abundant type in the public databases (Fig.4.2). This is partly due to the fact that the definition of an IS became implicitly coupled to the presence of a DDE Tpase, an idea probably reinforced by the similarity between Tpases of IS (and other TE) and the retroviral integrases (Fig.7.2)[6][7][8] particularly in the region including the catalytic site. More precisely, for these TE, the triad is DD(35)E in which the second D and E are separated by 35 residues. As more DDE transposases were identified, the distance separating the D and E residues was found to vary slightly (TABLE MGE transposases examined using secondary structure prediction programmes)[9]. However, for certain IS, this distance was significantly larger. In these cases, the Tpases include an “insertion domain” between the second D and E residues [9] with either α-helical or β-strand configurations (Fig.1.8.2). Although in most cases this is a prediction, it has been confirmed by crystallographic studies for the IS50 [β-strand[10] and Hermes [α-helical;[11] Tpases. The function of these “insertion domains” is not entirely clear[9].

Fig.7.2 DDE transposase Glu-Glu-Asp domain.Top: variation in spacing of the amino acid DDE triad and the downstream conserved lysine or arginine residues. The references are one of the first realizations that there is a significant similarity between eukaryotic and prokaryotic transposases. Below: the original structure of the HIV integrase catalytic core domain showing the position of the 4 relevant amino acids (green arrows), a single divalent metal cation (blue circle), and the projected position of bound DNA. (Figure thanks to F. Dyda).
Fig.7.3. The Transposase structures. Ribbon diagrams of aligned catalytic cores of four DNA transposases and of HIV-1 integrase. Residues shown in orange are the carboxylate active side residues, in green are the W residues of the Tn5 transposase and Hermes that are important in the reactions, in blue are the YRK residues of the YREK motif and in yellow is W298 of the Tn5 transposase. The insertion domains of the Tn5 transposase and Hermes are shown in red. The proteins are to scale. Adapted from Hickman et al., 2010.

Transposases examined by secondary structure prediction programs

Table 2. Adapted from Hickman et al. 2010, Integrating prokaryotes and eukaryotes: DNA transposases in light of structure. 1 Information on the number of copies within the host genome was obtained from ISfinder or the reference indicated by the asterisk. 2 Where indicated, the secondary structure predicts an insertion domain between β5 and α4 with predominantly either β-strands or α-helices. 3 Relevant references include reviews or papers that report the results of secondary structure prediction, report sequence alignments or consensus sequences, identify the DDE/D catalytic residues, or demonstrate that the element is active. The association of certain eukaryotic superfamilies to specific IS families is as per Feschotte and Pritham (2005) and references therein.
Family Element (or protein) analyzed Active or # copies in genome1 From secondary structure, type of DDE/D motif2 Relevant references3
IS1 IS1N >40* DD(24)E *Nyman et al., 1981; Ohta et al., 2002, 2004; Siguier et al., 2009
ISSto9 5 DD(20)E
IS1595 ISPna2 DD(36)N Siguier et al., 2009
ISH4 DD(36)E
IS1016C DD(34)E
IS1595 DD(35)N
ISSod11 13 DD(34)H
ISNWi1 DD(35)E
ISNha5 DD(33)E
Merlin: MERLIN1_SM consensus DD(36)E Feschotte, 2004
IS3 IS911 Active DD(35)E Polard and Chandler, 1995; Rousseau et al., 2002
IS481 IS481 ~100* DD(35)E *Glare et al., 1990; Chandler and Mahillon, 2002
IS4 IS50R Active PDB ID: 1muh Rezsöhazy et al., 1993; Davies et al., 2000
IS701 IS701 Active (15*) DD(β-strand)E *Mazel et al., 1991
ISRso17 7
ISH3 ISC1359 5 DD(β-strand)E
ISC1439A 13
IS1634 IS1634 Active (~30*) DD(β-strand)E *Vilei et al., 1999
ISMac5 7
ISPlu4 7
IS5 IS903 Active DD(65)E Derbyshire et al., 1987; Rezsöhazy et al., 1993; Tavakoli et al., 1997
PIF/Harbinger: PIFa (Z. mays) Active DD(59)E Zhang et al., 2001; Kapitonov and Jurka, 2004; Sinzelle et al., 2008
IS1182 IS660 3 DD(β-strand)E Takami et al., 2001
ISPsy6 14
IS6 IS6100 Active DD(34)E Martin et al., 1990; Mahillon and Chandler, 1998
IS21 IS21 Active DD(45)E Mahillon and Chandler, 1998; Berger and Haas, 2001
IS30 IS30 Active DD(33)E Caspers et al., 1984; Mahillon and Chandler, 1998
IS66 IS679 Active DD(α-helical?)E Han et al., 2001
ISPsy5 33
ISMac8 3
IS110 IS492 Active DEDD Perkins-Balding et al., 1999; Buchner et al., 2005
IS1111 20
IS256 IS256 Active DD(α-helical)E Mahillon and Chandler, 1998; Prudhomme et al., 2002
MuDr/Foldback (Mutator) Active Eisen et al., 1994; Babu et al., 2006; Hua-Van and Capy, 2008
IS630 ISY100 Active DD(34)E Doak et al., 1994; Feng and Colloms, 2007
Tc1/mariner: Mos1 (D. mauritiana) PDB ID: 2f7t Plasterk et al., 1999; Richardson et al., 2006
Zator: Zator-1_HM 36* DD(43)E *Bao et al., 2009
IS982 ISPfu3 5 DD(47)E Mahillon and Chandler, 1998
IS1380 IS1380A ~100* DD(β-strand)E *Takemura et al., 1991; Chandler and Mahillon, 2002
piggyBac (T. ni) Active DD(β-strand)D Cary et al., 1989; Sarkar et al., 2003; Mitra et al., 2008
ISAs1 ISAzo3 7 DD(β-strand)E/D?
ISL3 IS31831 Active DD(α-helical)E Suzuki et al., 2006
IS651 22
Tn3 Tn3 (E. coli) Active DD(α-helical?)E, DD(α-helical)E insertion Grindley, 2002
hAT Hermes Active PDB ID: 2bw3 Warren et al., 1994; Rubin et al., 2001; Hickman et al., 2005
CACTA CACTA1 (A. thaliana) En/Spm ZM Active DD(α-helical?)E/D? Miura et al., 2001; DeMarco et al., 2006
P Drosophila Active ? Rio, 2002
Transib Transib1_AG Consensus DD(α-helical)E Kapitonov and Jurka, 2005; Chen and Li, 2008
RAG1 (M. musculus) Active Kim et al., 1999; Landree et al., 1999; Lu et al., 2006
Sola Sola3-3_HM Multiple copies* DD(40)E *Bao et al., 2009


Major DDE transposition pathways

Although DDE-type transposons share basic transposition chemistry, different TE vary in the steps leading to the formation of a unique insertion intermediate (Fig.7.4)[5][9]. They catalyze the cleavage of a single DNA strand to generate a 3’OH at the TE ends which is subsequently used as a nucleophile to attack the DNA target phosphate backbone. This is known as the transferred strand. The variations are due to the way in which the second (non-transferred) strand is processed[5][12][13].

There are several ways in which second-strand processing can occur (Fig.7.4): for certain IS, the second strand is not cleaved but replication following the transfer of the first strand fuses donor and target molecules to generate cointegrates with a directly repeated copy at each donor/target junction. This is known as replicative transposition (e.g. IS6 and Tn3 families) or, more precisely, Target Primed Replicative Transposition (TPRT) (Fig.7.4 pathway a).

In the other pathways, the flanking donor DNA can be shed in several different ways: the non-transferred strand may be cleaved initially several bases within the IS prior to cleavage of the transferred strand [e.g. IS630 and Tc1[14][15][16] (Fig.7.4 pathway d); the 3’OH generated by the first-strand cleavage may be used to attack the second strand to form a hairpin structure at the IS ends liberating the IS from flanking DNA and subsequently hydrolyzed to regenerate the 3’OH known as conservative or cut-and-paste transposition (e.g. IS4 family;[17] (Fig.7.4 pathway f) and (Tn10 movie - see below) (Figs. IS4.5; IS4.6; IS4.7); the 3’OH of the transferred strand from one IS end may attack the other to generate a donor molecule with a single strand bridge which is then replicated to produce a double-strand transposon circle intermediate and regenerating the original donor molecule known as copy-out-paste-in or more precisely Donor Primed Replicative Transposition (DPRT) (e.g. IS3 family) [18] (Fig.7.3 pathway e) and (IS911 movie - see below); or the 3’OH at the flank of the non-transferred strand may attack the second strand to form a hairpin on the flanking DNA and a 3’OH on the transferred strand (at present this has only been demonstrated for eukaryotic TE of the hAT family and in V(D)J recombination [19]) (Fig.7.4 pathway g).

Clearly, many families produce double-strand circular intermediates, but this does not necessarily mean that they all use the copy-paste DPRT mechanism, since a circle could formally be generated by excision involving recombination of both strands[5]. These differences are reflected in the different IS families.

Fig.7.4. Major DDE transposition pathways: Dealing with the second strand. The color code is as follows: transposon DNA (green); flanking donor DNA (blue); target phosphates destined to be removed from the final liberated transposon (filled blue circles with a white “P”); phosphates destined to remain as 5′ transposon ends (open blue circles); the preferred stereoisomer, Sp or Rp, where known, is indicated within the circles; liberated 3′OH groups involved in strand joining reactions (open red circles); 3′OH destined to be removed from the liberated transposon (filled red circles); H2O is the attacking nucleophile in the hydrolysis reactions. (a) The Mu and Tn3 cleavage reactions. Note that the preferred stereo isomer has been demonstrated only for Mu and not for Tn3. (b) Tn7 cleavage reactions. Cleavage of the transferred strand (top of panel) is shown occurring prior to cleavage of the non-transferred strand (middle) leading to the liberation of the transposon from flanking donor DNA (bottom of panel), although this order of cleavage reactions has not been demonstrated experimentally. The two types of cleavage are catalyzed by different enzymes. (c) Retroviral “processing” reaction, equivalent to cleavage of the transferred strand. An initial transcription step from the integrated provirus is indicated. The RNA genome is then encapsidated with a second copy and undergoes reverse transcription following infection to generate the double-strand DNA integration intermediate. The intermediate is flanked by only short fragments of donor material and does not require second-strand processing for insertion. (d) Transposition by the members of the IS630 family and the Tc1/Mariner superfamily is initiated by cleavage of the non-transferred strand (top of panel) at several bases within the transposon end (middle) leaving these bases attached to the liberated flanks following cleavage of the transferred strand (bottom). (e) For IS911, IS2, IS3, and other members of the IS3 family, single-end hydrolysis occurs (top). The liberated 3′OH then directs a strand transfer reaction to the same strand, several bases 5′ to the other end of the element. This results in the formation of a single-strand circle, which is then resolved into a transposon circle by replication from the free 3′OH (filled red circle). Single-strand hydrolysis at each 3′ end within the circle generates a linear transposon which can then undergo integration. (f) The IS4 family and piggyBac have similar mechanisms. Following the initial nucleophilic attack on the Rp target phosphate, the liberated 3′OH attacks a Sp phosphate in a trans-strand transfer reaction to generate a hairpin intermediate, liberating the transposon from its flanking donor DNA and inverting the target phosphate to its Rp configuration. These then become the substrates for second hydrolysis. Note that the stereochemistry has been analyzed only in the case of Tn10. (g) Hermes and V(D)J transposition occurs by initial cleavage of the non-transferred strand (top). The liberated 3′OH on the donor flank then attacks the opposite strand (middle) to generate a hairpin structure on the donor flank (bottom). The stereochemistry has been analyzed for V(D)J only. Modified and reprinted from Turlan and Chandler (2000),
IS911 and Tn10 transposition mechanisms
IS911. Copy out - Paste in (column e in figure 8.3) Tn10. Cut and paste (column f in figure 8.3)

Groups with DEDD Transposases

A similar type of Tpase, known as a DEDD Tpase, is related to the Holiday junction resolvase, RuvC [20][21][22] but is at present limited to only a single known IS family (IS110). The organization of family members is quite different from that of the DDE ISs: they do not contain the typical terminal IRs of the DDE IS (although one subgroup, IS1111, carry sub-terminal IR) and do not generate flanking target DRs on insertion. This implies that their transposition occurs using a different mechanism as the DDE IS. It seems probable that an intermediate resembling a four-way Holliday junction is involved. Moreover, in contrast to the DDE transposases in which a DNA binding domain invariably precedes the catalytic domain, DEDD transposases appear to include a DNA binding domain downstream from the catalytic domain.


Groups with HUH Enzymes

TE encoding the second major type of Tpase, called HUH (named for the conserved active site amino acid residues H=Histidine and U=large hydrophobic residue )(Fig.7.1) and (Fig.7.5), has been identified more recently. HUH enzymes are widespread single-strand nucleases. They include Rep proteins involved in bacteriophage and plasmid rolling circle replication and relaxases or Mob proteins involved in conjugative plasmid transfer[23]. They are limited to two prokaryotic (IS91 and IS200/IS605; [24]) and one eukaryotic (helitron[25]) TE family.

As Tpases, they are involved in presumed rolling circle transposition and also in single-strand transposition (see [24][5]). Not only is the transposition chemistry radically different to that of DDE group elements, since it involves DNA cleavage using a tyrosine residue and transient formation of a phospho-tyrosine bond, but the associated transposons have an entirely different organization and include sub-terminal secondary structures instead of IRs (see IS families [24]). Note that these Tpases are not related to the well-characterized tyrosine site-specific recombinases such as phage integrases.

There are two major HUH Tpase families: Y1 and Y2 enzymes (Fig.7.1)(see [23]) depending on whether there is a single or two catalytic Y residues. One family includes IS91-family transposases[26][27], the other includes IS200/IS605 transposases[28][29][30][31][32][33]. Although these enzymes use the same Y-mediated cleavage mechanism, IS200/IS605 family Y1 transposases and IS91 transposases appear to carry out the transposition process in quite different ways. Neither carries terminal IRs nor do they generate DRs on insertion. Members of these families transpose using an entirely different mechanism to IS with DDE transposases[34][35]. The members of the IS91 insertion sequence family[36][37], are related to a newly defined group, the ISCR[38] (see “IS91-related ISCRs”) and with eukaryotic helitrons (Fig.7.1)[39]. These IS carry sub-terminal sequences which are able to form hairpin secondary structures (Fig.3.2). This is particularly marked in the IS200/IS605 family elements and, at least in the case of this family, it is these structures that are recognized by the transposase[24].











Fig.7.5. The HUH enzymes. Organization of representative HUH domain-containing proteins is shown; they contain HUH, helicase, oligomerization (OD) and proposed Zn - binding (not necessarily structurally related) domains. The length of each protein is indicated in numbers of amino acids, and those proteins for which HUH domain structures are available are indicated with an asterisk; the HUH motif data are from Koonin & Ilyina Biosystems 30, 241–268 (1993) (motif 2) and Garcillan-Barcia et al., FEMS Microbiol. Rev. 33, 657–687 (2009) (motif III); the Y motif data are from Koonin & Ilyina Biosystems 30, 241–268 (1993) (motif 3) and Garcillan-Barcia, et al;, FEMS Microbiol. Rev. 33 , 657–687 (2009) (motif I). The assigned domain organizations are taken from phage φ X174 protein A (gpA) (Boer et al. EMBO J. 28, 1666–1678 (2009)), AAV Rep78 (Smith et al., J. Virol. 71, 4461–4471 (1997)), tomato yellow leaf curl virus (TYLCV) Rep (Campos-Olivas et al Proc. Natl Acad. Sci. USA 99, 10310–10315 (2002)) , plasmid pMV158 RepB (Boer et al. EMBO J. 28, 1666–1678 (2009)), plasmid R388 TrwC (Guasch et al. Nature Struct. Biol.10, 1002–1010 (2003)), plasmid RSF1010 MobA (mobilization protein A) (Monzingo et al. J. Mol. Biol. 366, 165–178 (2007)), transposases from the insertion sequences IS608 (Ronning et al. Mol. Cell 20 , 143–154 (2005)), IS91 and insertion sequence with a common region 1 (ISCR1) (S. Messing, A.B.H. and F.D., unpublished observations), and HeliBat1 (a consensus sequence from a bioinformatic prediction).

Groups with S-Transposases

The third transposase family is represented by IS607 which carries a Tpase closely related to serine recombinases such as the resolvases of Tn3 family elements. Little is known about their transposition mechanism. However, it appears likely, in view of the known activities of resolvases, that IS607 transposition may involve a double-strand DNA intermediate (Grindley cited as pers. comm. in [40]) see also [41] (Fig.7.1).

Groups with Y-Transposases

Finally, tyrosine site-specific recombinases of the bacteriophage integrase (Int) type are often associated with conjugative transposons (Integrative Conjugative Elements or ICE)( IS related to ICE) and are considered to be Tpases. However, at present there are no known IS which use this type of enzyme (Fig.7.1).

Bibliography

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