IS Families/IS30 family

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General features and Original Identification

IS30 was identified as an insertion into the phage P1 genome[1][2].

Distribution

The IS30 family currently comprises more than 100 members from 94 members from nearly 80 bacterial species and an example, ISC1041, has also been found in the Archaea[3]. IS30-like Tpases have also been found as integral parts of certain Integrative Conjugative Elements (ICE) from Staphylococcus aureus (MRSA)[4]. An open reading frame found originally in a Spiroplasma citri phage (ΦSc1) but since identified also in the Spiroplasma citri genome is distantly related to the family.

Organization

IS30 family members have lengths of between 1027 bp (e.g. IS1070) and 1636 bp (e.g. ISCg2) with a single orf of between 293 and 398 codons spanning almost the entire length. The termination codon is generally very close to the right end. Alignment of the putative Tpases reveals a well-conserved DD(33)E motif.

Family members can activate neighboring genes by creation of a hybrid promoter on insertion next to a -10 promoter element[5][6][7][8].

The Tpases show several well-conserved regions. One, in the N-terminus includes a potential helix–turn–helix (HTH) motif, which, in the case of IS30, is responsible for IR binding[9][10]. Another in the C-terminal region contains the DD(33)E motif (Fig. IS30.1).

Fig. IS30.1. Common IS30 organization. Top: SnapGene cartoon of IS30 organization. Bottom: Left (IRL) and right IRR inverted terminal repeats are shown in WebLogo format (Crooks et al., 2004).

The terminal IRs are in the range of 20-30 bp and exhibit significantly conserved sequence signatures (Fig. IS30.1). The tips of the elements, as defined by the various authors, show significant sequence variation, although in most elements the IR has not been experimentally confirmed. Where it has been determined, 2 bp or 3 bp direct target repeats are generated on insertion, but there are several exceptions in which the DR is between 12 and 32 bp. [e.g. IS1630, IS1470, IS658, ISApl1, ISL7, ISLpl1[10]]. One member of this family, IS1630 (1377bp) from Mycoplasma fermentans is flanked by long but variable DRs of between 19 and 26bp[11].

Presence in Compound Transposons

IS30 is known to function in a compound transposon structure[12] and various IS30 family members also have been identified as part of composite transposons. In particular, Tn6330 which is composed of two copies of ISApl1 flanking the colistin resistance gene, mcr-1[13][14][15].

IS30

Of the different members of this family, IS30 is the best characterized. It is 1221 bp long with 26 bp terminal IRs and mediates several types of DNA rearrangements including simple insertion, cointegrate formation, deletion and inversion[2][16][17]. It shows pronounced insertion specificity and generates DRs of 2 bp. It terminates with the dinucleotide 5'-CA-3'[18] although many other members of the family do not. The single long orf is preceded by a relatively weak promoter (p30A) capable of driving Tpase expression with its -35 hexamer within IRL[19] and contains a weak internal transcription terminator. The transposase is predicted to include two N-terminal HTH motifs (Fig. IS30.2) and show significant homology to FixJ, a Sinorhizobium meliloti transcriptional regulator[10]. Premature transcription termination at this site could lead to the formation of Tpase molecules truncated at their C-terminal end carrying the catalytic DDE motif. Since the specific DNA binding domain which recognizes the terminal IRs is located in the N-terminal third of the protein[9], the potential truncated derivatives may lack the catalytic domain and regulate transposition activity by competition or interaction with a full-length Tpase. This arrangement may play the same role at the transcriptional level as does frameshifting at the translational level for certain other elements.

Fig. IS30.2. Predicted secondary structure of the IS30 transposase N-terminus. Alignment of IS30 family transposases (TPase), secondary protein structure, and mutagenesis. The alignment of the N-terminal region of five IS30 family TPases is presented. Conserved amino acids are marked with grey boxes and the consensus sequence is also shown below. a-Helices of the IS30 TPase (the vertical arrows show positions of point mutations used in functional analysis)

A second weak promoter (p30C) located on the opposite strand upstream of a short orf has been detected[19] and it has recently been shown that a small 150 nucleotide transcript driven from this promoter and contained entirely within the Tpase transcript acts as an antisense control by reducing translation of the Tpase mRNA[20].

The founding member of the family, IS30, is also the best characterized at the mechanistic level[9][16][21][22][23][24][25][26] and an in vitro transposition system has been developed[27]. This 1221 bp long Escherichia coli element belongs to a growing class of ISs known to transpose through an intermediate formed by abutting the IRs, Donor Primed Transposon Replication. Here the IR are separated by 2 bp[5][16][23]. Such an IR junction can be created by formation of a dimer of two directly repeated IS copies or by the formation of transposon circles. Both IS mini-circles and dimers have been observed. IR–IR junctions have also been detected in some other IS30 family members such as IS18[7], IS4351[28] and IS1470[29]. A structure in which two IS30 ends are linked by a single strand bridge (forming a figure of eight structure on a circular plasmid), has been identified[27].

As in the case of IS21 and IS3 families, the assembly of abutted IRL and IRR copies create a strong promoter. In a tandem dimer of the element, this may result in increased expression of the Tpase from the downstream copy[5]. The IRL-IRR junction is also recombinationally unstable. It promotes transposition reactions at high frequency in vivo [16] presumably in a similar way to the equivalent junction of IS21 (see "IS21 family"). The activity of the junction appears maximal when the spacer between the abutted ends is 2 bp (the length of target duplications introduced when IS30 inserts). Lower activities are obtained with 1 and 3 bp spacers while little or no activity is observed for 0 bp or >3bp (T. Naas and W. Arber, pers. comm.). Strong evidence has recently been presented indicating that donor plasmid dimerization is followed by interaction of one appropriately oriented end from each IS copy to form an abutted IS intermediate (see Fig. IS30.3). The IS junction in this intermediate is highly active in transposition and plays an important role in transposition of IS30[23].

Fig. IS30.3. Artificial plasmid dimer: thin line, replicative plasmid; thick line, non-replicative DNA segment; boxes, IS30; triangles, terminal IRs. Ap and Km, genes for resistance to ampicillin and kanamycin. Instead of attacking the opposite IR to generate a circular IS copy, one IR of the “top” IS copy is shown to attack an IR of the “bottom” IR copy to delete the intervening DNA (thick line) generating a dimeric IS with an active (unstable) IR junction.

Like IS21[30] and IS911[31], IS30 shows a preference for insertion next to nucleotide sequences resembling its ends[22]. Furthermore, this region has been delimited approximately to the Tpase binding site. In addition, preferential insertion into a site in bacteriophage l (LHS) and P1 (OHS) has been observed both in E.coli [16] and Salmonella[32]. These sequences are somewhat degenerate palindromes characterized by a 24 bp symmetric consensus[33] (Fig. IS30.4). The sequence relationship between these various hotspots has yet to be explored. A similar type of insertion specificity was observed for IS1655 from Neisseria meningitis[26] (Fig. IS30.5). Another IS30 family member, ISCg2 from Corynebacterium glutamicum, has also been shown to insert into a relatively well defined sequence which exhibits some palindromic symmetry[34] while yet another, IS1630 from Mycoplasma fermentans, appears to show a preference for rather long target with extensive palindromic sequences[11].

Fig. IS30.4. The consensus sequence of IS30 insertions in phages and plasmids. A. The consensus sequence of IS30 insertion sites. The positions and symmetry of the Consensus of Insertions in Phages/Plasmids (CIP) sequence are also indicated. B. The sequence of POHS and LSHS hot‐spots and their homology to the CIP consensus. C. The sequence of ‘half’ POHS sites. n, consensus cannot be determined; R, A or G; Y, T or C; W, A, or T. Capital letters correspond to bases matching the consensus. The fractions give the proportion of matching bases to the number of conserved positions in CIP.
Fig. IS30.5. The consensus of 110 IS1655 target sequences comprising: 38 IS1655 insertions in public databases; 72 target sites of IS1655 reference copy isolated from different plasmids and the E. coli chromosome. The target sites were generated by removing the entire IS1655 copy and one of the 3 bp direct repeats bracketing the element in the original sequence. The sequences were oriented according to the orientation of the IS1655 copy. Originally the left half of each target sequence flanked the IRL and the right half flanked the IRR of the element. Conserved bases were not found out of the 9 bp region. The sequence logo was generated for the central 27 bp of target sites by the WebLogo server (http://weblogo.berkeley.edu/).

ISApl1

ISApl1 plays an important role in transmission of resistance to the last resort antibiotic, colistin [35][36][37][38][39][40][41]. It was originally identified in Actinobacillus pleuropneumoniae from pigs[42] and has typical IS30 family characteristics: 1070 bp long with a 924 bp transposase orf and flanked by 27 bp inverted repeats. Four copies occurred in the original AP76 strain, one of which interrupts the apxIVA toxin gene. It was also reported to be present in certain field isolates but not in the type strain. All four insertions generate a two base pair DR and occur in an AT rich region with some palindrome-like characteristics and a central GC rich region (see Fig. IS30.6) similar to that observed for IS1665[26]. Its transposase is very similar to that of IS30, especially around the active site.

Fig. IS30.6. Weblogo of sequences flanking 23 ISApl1 copies. The figure illustrates the conservation observed in the target sequence of a number of ISApl1 copies.

PCR analysis demonstrated the presence of a junction fragment in which IRL and IRR are separated by a GG dinucleotide. This is the DR observed at the ISApl1 insertion site in A. pleuropneumoniae downstream of a bla gene but is not present at the other three insertion sites in this strain. The presence of this junction fragment suggests that ISApl1, like IS30 and IS1665, occurs using a circular DNA intermediate during transposition.

Following the initial report in 2016 of resistance to a last resort antibiotic, the polymyxin colistin, by a transmissible plasmid-associated mcr-1 gene [36], it was rapidly recognized (within the year) that the gene, which encodes a Phosphoethanolamine Transferase[36], was present in Enterobacteriaceae from five continents: Asia, Europe, Africa, South America, and North America (reviewed in [43]). Based on the analysis of 77 mcr-1-containing sequences (of which 19 were too fragmented to be useful) representing every unique sequence in NCBI as of August 2016, a common 2,607-bp DNA segment was identified that in many cases is flanked on one or both ends by ISApl1[14]. This fragment included the mcr-1 gene together with a truncated copy of a gene called pap2. This analysis led to the proposal that mcr-1 was transmitted by an ISApl1 composite transposon, later called Tn6330[15] which has, in some cases, subsequently lost one or both ISApl1 copies. Analysis of Tn6330 transposition has identified the expected transposition intermediate[44]: a transposon circle which carries a pair of abutted IS copies (as shown for IS30[23]; Fig. IS30.3). A second structure found in the study, a circular form with only a single IS copy may be equivalent to one of the transposition related deletion products described for IS30 [23] or simply by homologous recombination between the pair of directly repeated ISApl1. This was also observed in another study[15].

Further analysis with an enlarged database [13] provided further support for this and resulted in a model for the mobilization of mcr-1 from the chromosome of a species closely resembling Moraxella sp. MSG13-C03 by insertion of ISApl1 copies upstream and downstream (Fig. IS30.7), transmission by transposition to a target plasmid followed by interbacterial transfer and acquisition by additional conjugative plasmids. The sites of insertion were as expected for ISApl1 insertion sites (Fig. IS30.6), an observation which has been extensively confirmed[44]. The full transposon was then proposed to decay by deletion of the downstream and/or upstream ISApl1 copies leaving Tn6330 derivatives carrying a single downstream or upstream IS copy or devoid of both IS copies (Fig. IS30.7). Based on the transposition mechanism of IS30 family members, and on the observation that, although the deletion endpoints were variable from case to case, the length of the deletion was remarkably constant (Fig. IS30.8) representing the exact IS length, it was further proposed that IS deletion occurred by frequent abortive IS transposition (Fig. IS30.9 and Fig. IS30.10). IS30 family transposition appears to occur by a copy-out-paste-in mechanism which involves replication (Fig. IS30.9 left). In the deletion model, strand-switching between micro homologies during the replication step (Fig. IS30.9 right) would lead to the “looping out” of the IS rather than replication through to the opposite end. This could lead to removal of the IS copy during further plasmid replication [13]. This model is supported by data obtained several decades ago in which similar loss of IS30 was shown to occur with relatively high frequency and involve microhomologies[45]. Unfortunately, a more recent study that analyzed the stability of Tn6330 did not directly address the loss of flanking ISApl1 or the necessity of transposition enzymes or intact terminal IRs [15].

Fig. IS30.7. The birth and demise of Tn6330. A schematic representation of the birth of Tn6330 following insertion of two copies of ISApl1 into the chromosome of a species closely resembling Moraxella sp. MSG13-C03 followed by successive decay of the transposon due to the loss of one ISApl1 copy and then both ISApl1 copies are shown. The conserved AT and CG dinucleotides that were formed during the first sequestration of the mcr-1 region, and that are now found on the IE of all instances of Tn6330, are highlighted in bold.
Fig. IS30.8. Distribution of the different deletion sizes following loss of the downstream ISApl1 in 19 transposon sequences. The average deletion size is 1,069.8 bp (Standard deviation: 2.4).
Fig. IS30.9. Deletion of the upstream ISApl1 copy. Alignment showing the decay of multiple different instances of Tn6330 (top) into the corresponding double-deletion structures formed (bottom of figure), aligned with their respective empty sites (below, highlighted in gray; see the text for details). “Hypothetical” Tn6330 insertions constructed from known empty site plasmids, the corresponding double-deletion structures, and the sequence of Tn6330 are indicated with an asterisk. Dashes were inserted to maintain sequence alignment. The bases upstream and downstream of the deletion that is retained after ISApl1 loss are highlighted in red and blue, respectively. The deletion joints upstream and downstream of the ISApl1 are encased in a black rectangle. The bases upstream and downstream of the deletion that is retained after ISApl1 loss are highlighted in red and blue, respectively, while the remaining copy of the deletion joint that is retained after the two ends are joined following ISApl1 excision is highlighted in green and encased in a black rectangle.


Fig. IS30.10. A mechanism for ISApl1 deletion. The left-hand panel shows part of the ISApl1 transposition cycle. The IS is shown in green and the donor plasmid backbone in black. The terminal IRs are indicated by black boxes and the tips of the IS as green circles. (A to C) The IS ends in the donor plasmid (A) undergo synapsis (B), and one or other end undergoes cleavage to generate a 3′OH which then attacks the opposite end at a position several nucleotides into the donor backbone to generate a molecule in a figure-eight formation in which the two IRs are joined by a single-strand bridge (C). (D) A 3′OH generated on the donor plasmid is then used to replicate the IS, generating a double-strand circular transposition intermediate. A strong promoter is generated by the juxtaposition of the two IS ends which drives high levels of transposase expression, facilitating insertion into a suitable target DNA (not shown). The right panel (top) shows the double-strand sequence of the IS ends in IncI2 plasmid pMCR-M17059 as an example. The middle panel presents the structure of the single-strand bridged molecule (as described for panel C) that is shown in the left panel. IS ends are boxed in green. The 3′OH generated in the donor plasmid DNA is indicated by a red dot and the corresponding 5′ phosphate at the other IS end by a black dot. The blue arrow indicates the direction of transposition-associated replication. The deletion joint is shown in blue. The sequence remaining after deletion (bottom) representing plasmid pSCS23 is composed of the bold black characters together with one of the blue tetranucleotide sequences.


Structural studies

There are no structural data available at present for any members of this family, although recent results obtained with an IS from another family, ISCth4 from the IS256 family, which also undergoes copy-out-paste-in transposition has provided some insights [46]. In accord with this type of mechanism, crystal structures of ISCth4 transposase bound to three different substrates show a transposase dimer bound asymmetrically to a single DNA substrate: a pre-reaction substrate with IRR together with its flanking DNA, a pre-cleaved complex in which the IRR flank had been removed and a strand transfer complex including an abutted IRR and IRL separated by a gapped 6 base pair linker (Fig. IS256.8). It is important to note that IS256 family transposases carry an alpha-helical insertion domain which separates the catalytic domain into two segments. This domain plays an important role in directing different DNA segments during the reaction. IS30 family transposases carry an uninterrupted catalytic domain without the alpha-helical insertion domain implying that the atomic details of the process will differ.

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