General Information/IS and Gene Expression

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Another important aspect of IS impact on their bacterial hosts is their ability to modulate gene expression. In addition to acting as vectors for gene transmission from one replicon to another in the form composite transposons (two IS flanking any gene; Fig.2.3) and tIS (Fig.8.1) and their ability to interrupt genes, it has been known for some time[1][2] that IS can also activate gene expression. This capacity has recently received much attention due to the increase in resistance to various antibacterials[3][4][5], a worrying public health threat[6][7].

They can accomplish this in two ways: either by providing internal promoters whose transcripts escape into neighboring DNA[2][8][9][10] or by hybrid promoter formation. Many IS carry -35 promoter components oriented towards the flanking DNA (Fig.18.1). In a number of cases this plays an important part in their transposition since a significant number of IS transposes using an excised transposon circle (Fig.18.1) with abutted left and right ends. For these IS, the other end carries a -10 element oriented inwards towards the Tpase gene. Together with the -35, this generates a strong promoter on formation of the circle junction to drive Tpase expression required for catalysis of integration (Fig.18.2) [11][12][13][14]. Thus if integration occurs next to a resident -10 sequence, the IS -35 sequence can contribute to a hybrid promoter to drive expression of neighboring genes [see [15]]. At present this phenomenon had been reported to occur with over 30 different IS in more than 17 bacterial species[16][17] (Table IS and Gene Expression below). Indeed, specific vector plasmids have been designed to identify activating insertions (e.g. [18]).

IS activity can affect efflux mechanisms resulting in increased resistance: IS1 or IS10 insertion can up-regulate the AcrAB-TolC pump in Salmonella enterica[19]; IS1 or IS2 insertion upstream of AcrEF[20][21] and IS186 insertional inactivation of the AcrAB repressor, AcrR, in Escherichia coli [20], all lead to increased resistance to fluoroquinolones. Insertional inactivation of specific porins can also play a significant role[22].

Fig.18.1. Copy out paste in (DDE).Left column. Illustrates the copy out paste in the transposition mechanism. The transposon is represented as a yellow line. Flanking sequences in the donor molecule are blue. Flanking sequences in the target molecule are green. Red circles indicate 3′OH moieties generated by Tpase-catalyzed hydrolysis at the transposon end(s). Red boxes indicate target DNA flanks that are duplicated on insertion. Top to bottom: Tpase catalyzed cleavage at the 3′ transposon ends using H2O as the nucleophile. Liberated 3′OH attack the opposite end to create a bridged molecule which then undergoes replication (dotted line) to generate a circular transponso copy and regenerate the donor molecule. The circle intermediate undergoes cleavage to generate two 3'OH ends which attack the target DNA in a staggered way resulting in integration. Repair at each end then generates the direct target repeat characteristic of many transposons. Right column. Formation of hybrid promoters by copy out -paste in transposition. The left and right terminal inverted repeats of the IS, IRL ,and IRR, are shown as a square and pointed box respectively. The component –10 and –35 promoter elements of pjunc within these ends are also shown together with the weak pIRL promoter and the direction of transcription of the transposase. In a first step, single-strand cleavage and transfer from one IR to the other is catalyzed by OrfAB produced from the weak pIRL promoter. This is indicated at the top of the figure by the curved arrow. In this case, the right end (IRR) is shown attacking the left end (IRL). The resulting figure-eight form is drawn below and shows the free 3’OH group generated on the flanking donor DNA sequence. In a second step, second-strand circularization occurs by an as yet undetermined mechanism involving host functions but independently of transposon proteins [Turlan et al., 2000 ]. The resulting IRR-IRL junction carries suitably placed -35 and –10 hexamers, separated by a canonical 17 bp spacer and form a strong pjunc (bold arrow) promoter able to promote high levels of production of IS911 proteins. Integration of the circle results in disassembly of the promoter restoring low levels of expression from pIRL. Insertion upstream of a resident -10 promoter element can bring the IR-associated -35 element at the correct distance to form a promoter and activate a downstream gene.
Fig.18.2. Promoter Activities of junction fragments from different IS circles.Results of measurements of activities of 9 IS circle junctions when placed upstream of a beta-galactosidase gene.

IS and Gene Expression

Table. IS and gene expression.
IS family IS name Mechanism Gene(s) affected Organism Reference Clinical/Experimental
IS1 IS1 Cointegrate EmR Escherichia coli [23] C?
Copy-paste circles blaTEM-1 [15] E
acrEF pump Salmonella enterica [19] E
IS3 IS2 Copy-paste circles gal Escherichia coli [24][25] E
gal [23][2] E
argE [26][20] E
EmR C?
blaampC E
acrEF pump E
IS3 Copy-paste circles argE Escherichia coli [2] E
argE [8] E
citT [27] E
IS981 Copy-paste circles ldhB Lactococcus lactis [28] E
IS6110 Copy-paste circles Rv2280 and PE-PGRS gene, Rv1468c Mycobacterium tuberculosis [29] E
ISKpn8 Copy-paste circles blaKCP-2 Escherichia coli, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, and Klebsiella oxytoca [30] C
IS4 IS10 Cut-paste (hairpin) his Salmonella typhimurium [31] E
Cut-paste Escherichia coli [32] E
Cut-paste acrEF pump Salmonella enterica [19] E
IS50 Cut-paste (hairpin) aph3’II Escherichia coli [33] E
IS1999 blaVEB-1 Pseudomonas aeruginosa [4] C
blaVEB-1/blaOXA-48 Escherichia coli [3] C
ISPa12 blaPER-1 Salmonella enterica, Pseudomonas aeruginosa, Providencia stuartii, Acinetobacter baumannii [34] C
ISAba1 blaampC Acinetobacter baumannii [35][36][37] C
blaOXA-51/blaOXA-23 [38] C
IS5 IS5 EmR Escherichia coli [23] C?
ISFtu2 general Francisella tularensis [39] Natural isolate
ISVa1 (iron uptake) Vibrio anguilarum [40] Natural isolate
IS1168 nimA, nimB Bacteroides sp. [41] C
IS1186 cfiA Bacteroides fragilis [42][43] C
IS402 bla Pseudomonas cepacia [44] E
IS6 IS257 Cointegrate dfrA Staphylococcus aureus [45] C
IS257 Cointegrate tet Staphylococcus aureus [46]
IS1008 blaOXA-58 Acinetobacter baumannii [47]
IS26 aphA7, blaS2A Klebsiella pneumoniae [48]
blaSHV-2a Pseudomonas aeruginosa [49]
IS140 aac(3)-III and -IV [50]
IS21 ISBf1 Copy-paste circle cepA Bacteroides fragilis [51] C
ISKpn7 blaKPC Klebsiellea pneumonia [52]
IS30 IS30 Copy-paste circle galK Escherichia coli [53] E
IS18 aac(6’)-Ij Acinetobacter sp. [54] C
blaOXA257 [55]
IS4351 ermF Bacteroides fragilis [56] C
cfiA [5]
IS1086 cnrCBAT (ZnR) Cupriavidus metallidurans E
IS256 IS256 Copy-paste circles mecA Staphylococcus sciuri [57][58]
llm Staphylococcus aureus
IS1490 Burkholderia cepacia [59]
IS406 Burkholderia cepacia [44] E
IS481 IS481 Copy-paste circles katA Bordetella pertussis [60]
ISRme5 cnrCBAT (Zn R) Cupriavidus metallidurans [61] E
IS630 ISFtu1 Tc-like general Francisella tularensis [39] Natural isolate
IS982 IS1187 cfiA Bacteroides fragilis [42] E+C
[5][62][63] C
IS982 citQRP Lactococcus lactis [64]
IS1380 ISBf12 cfiA Bacteroides fragilis [5] C
IS612 [63]
IS613 [63]
IS614 [5][63][65]
IS1188 [62]
IS942 [62]
ISEcp1 blaCTX-M-15 Enterobacteriaceae [66]
blaCTX-M-17 Klebsiella pneumoniae [67]
blaCTX-M-19 Klebsiella pneumoniae [34]
blaCTX-M Kluyvera ascorbata [68]
rmtC Escherichia coli [69]
IS1187 cfiA Bacteroides fragilis [62]
ISL3 ISSg1 Copy-paste circles sspB (surface antigen) Streptococcus gordonii [70]
IS1411 pheBA Pseudomonas putida [71]
ISAs1 IS1548 lmb (lamelin binding) Streptococcus agalactiae [72]
nd Acinetobacter baumannii [35] C
ISNYC IS403 bla Burkholderia cepacia [44] E


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