UmuD and RecA Directly Modulate the Mutagenic Potential of the Y Family DNA Polymerase DinB

Godoy, Veronica G.; Jarosz, Daniel F.; Simon, Sharotka M.; Abyzov, Alexej; Ilyin, Valentin A.; Walker, Graham C.

doi:10.1016/j.molcel.2007.10.025

Cited by 104 publications

(213 citation statements)

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“…Although all Acinetobacter strains possess a dinP gene, only A. ursingii possesses a umuD-dinP locus, raising the possibility that this unique locus might be associated with its capacity to conduct UV-induced mutagenesis. The UmuD 2 homodimer can interact with DinP (DNA pol IV), and alter its mutagenic activity in E. coli (Foti et al, 2010;Godoy et al, 2007). Supporting this possibility is the distinctiveness of this dinP-linked umuD allele, as strongly supported by bootstrap analysis (Fig.…”

Section: Resultsmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

“…Two cleaved UmuD9 molecules then associate with UmuC to form DNA polymerase V, which carries out error-prone, trans-lesion DNA replication (SOS mutagenesis) (Reuven et al, 1999;Tang et al, 1999). Another errorprone polymerase commonly involved in SOS mutagenesis as part of the DNA damage response is DinP (also called DinB), DNA polymerase IV, which can function either by itself (Kim et al, 1997) or with UmuD (Foti et al, 2010;Godoy et al, 2007).Variation on the standard E. coli-developed model of DNA damage responses is shown by differences in SOS-induced genes, the number or presence of LexA proteins, and specific SOS box sequences in genera such as ADP1 responds to DNA damage differently than E. coli, with induction of its recA gene not dependent on RecA function (Rauch et al, 1996). Many other changes are associated with the umuDC operon.…”

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confidence: 99%

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Diverse responses to UV light exposure in Acinetobacter include the capacity for DNA damage-induced mutagenesis in the opportunistic pathogens Acinetobacter baumannii and Acinetobacter ursingii

et al. 2012

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Error-prone and error-free DNA damage repair responses that are induced in most bacteria after exposure to various chemicals, antibiotics or radiation sources were surveyed across the genus Acinetobacter. The error-prone SOS mutagenesis response occurs when DNA damage induces a cell's umuDC-or dinP-encoded error-prone polymerases. The model strain Acinetobacter baylyi ADP1 possesses an unusual, regulatory umuD allele (umuDAb) with an extended 59 region and only incomplete fragments of umuC. Diverse Acinetobacter species were investigated for the presence of umuDC and their ability to conduct UV-induced mutagenesis. Unlike ADP1, most Acinetobacter strains possessed multiple umuDC loci containing either umuDAb or a umuD allele resembling that of Escherichia coli. The nearly omnipresent umuDAb allele was the ancestral umuD in Acinetobacter, with horizontal gene transfer accounting for over half of the umuDC operons. Despite multiple umuD(Ab)C operons in many strains, only three species conducted UV-induced mutagenesis: Acinetobacter baumannii, Acinetobacter ursingii and Acinetobacter beijerinckii. The type of umuDC locus or mutagenesis phenotype a strain possessed was not correlated with its error-free response of survival after UV exposure, but similar diversity was apparent. The survival of 30 Acinetobacter strains after UV treatment ranged over five orders of magnitude, with the Acinetobacter calcoaceticus-A. baumannii (Acb) complex and haemolytic strains having lower survival than non-Acb or non-haemolytic strains. These observations demonstrate that a genus can possess a range of DNA damage response mechanisms, and suggest that DNA damage-induced mutation could be an important part of the evolution of the emerging pathogens A. baumannii and A. ursingii. INTRODUCTIONWhen bacteria are exposed to DNA-damaging agents, such as UV light or chemical mutagens, a wide variety of SOS response genes (genes that play critical roles in repairing damaged DNA) are specifically induced (Friedberg et al., 1995;Walker, 1996). In the model developed by experimentation in Escherichia coli, SOS genes are negatively regulated by the LexA repressor binding to the SOS box in the promoter (Mount et al., 1972). DNA damage causes the activation of RecA, which facilitates LexA self-cleavage and releases the repression of SOS genes such as umuDC (Little et al., 1980;1981). UmuD initially causes a pause in cell division while DNA repair and replication occurs (Opperman et al., 1999). However, within minutes, UmuD homodimerizes and carries out intermolecular self-cleavage, facilitated by activated RecA* interaction (Nohmi et al., 1988). Two cleaved UmuD9 molecules then associate with UmuC to form DNA polymerase V, which carries out error-prone, trans-lesion DNA replication (SOS mutagenesis) (Reuven et al., 1999;Tang et al., 1999). Another errorprone polymerase commonly involved in SOS mutagenesis as part of the DNA damage response is DinP (also called DinB), DNA polymerase IV, which can function either by itself (Kim et al., 1997) or with U...

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Section: Resultsmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Diverse responses to UV light exposure in Acinetobacter include the capacity for DNA damage-induced mutagenesis in the opportunistic pathogens Acinetobacter baumannii and Acinetobacter ursingii

et al. 2012

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“…These observations are consistent with RecA facilitating takeover of rapid Pol III*-replisomes by slow TLS Pols. Furthermore, Pol IV is known to perform −1 frameshifts that are suppressed by UmuD (uncleaved form) in a RecA-dependent manner (53). Hence, yet other proteins may be expected to modulate the actions of Pol IV, in addition to RecA.…”

Section: Discussionmentioning

confidence: 99%

RecA acts as a switch to regulate polymerase occupancy in a moving replication fork

Indiani

Patel

Goodman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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This report discovers a role of Escherichia coli RecA, the cellular recombinase, in directing the action of several DNA polymerases at the replication fork. Bulk chromosome replication is performed by DNA polymerase (Pol) III. However, E. coli contains translesion synthesis (TLS) Pols II, IV, and V that also function with the helicase, primase, and sliding clamp in the replisome. Surprisingly, we find that RecA specifically activates replisomes that contain TLS Pols. In sharp contrast, RecA severely inhibits the Pol III replisome. Given the opposite effects of RecA on Pol III and TLS replisomes, we propose that RecA acts as a switch to regulate the occupancy of polymerases within a moving replisome. Previous studies have shown that all three Pols function at replication forks with DnaB helicase, primase, the β sliding clamp, and the clamp loader (2). Bulk chromosome replication is performed by Pol III, and the mechanism that regulates the access of TLS Pols to the replisome is largely unexplored.Heavy DNA damage in E. coli induces the SOS response, which slows down chromosomal replication (3) and expresses over 40 proteins that aid cell survival and enable genome replication to continue (4, 5). Induction of the SOS response requires formation of ssDNA by replication forks to which the cellular recombinase, RecA, binds. The binding of RecA to ssDNA facilitates RecAmediated self-cleavage of the LexA repressor, thereby activating the SOS response genes (6). Among these are TLS Pol II (polB) and TLS Pol IV (dinB), which are rapidly (<5 min) up-regulated during the SOS response (7-10). TLS Pol V (UmuD′ 2 C) is induced late (≥45 min) and requires RecA bound to ssDNA (RecA*) for synthetic activity (8,11,12). Pol IV and Pol V belong to the Yfamily Pols (1), whereas Pol II, even though involved in TLS and mutagenesis, is a B-family polymerase (13).During normal chromosome duplication, the intracellular levels of Pols II and IV are not sufficient to take over Pol III-based replisomes (2). Upon DNA damage, the induced levels of TLS Pols take over the cellular replicase (2, 14, 15). Our previous studies have shown that Pols II and IV replace Pol III within the replisome without causing fork collapse, as they preserve the DNAbound helicase and sliding clamp to form TLS Pol replisomes (2). Pol II and Pol IV replisomes progress at significantly slower rates than the intrinsic rate of DnaB helicase, and thus regulate the speed of helicase unwinding. Slower fork progression may give the cell additional time to repair DNA lesions using normal repair processes (e.g., nucleotide excision repair), thereby preventing direct encounters of the replication fork with DNA lesions.It has been suggested that polymerase selection at the replication fork is mainly guided by mass action dictated by the concentration of each polymerase and its affinity for the clamp (1,14,16,17). However, the findings of this report demonstrate that RecA adds an additional level of control, acting as a switch that regulates DNA polymerase access to the replicat...

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“…26 Alternatively, the inherent instability of RecA mediated D-loops may contribute to low-fidelity DNA synthesis. RecA-mediated D-loops are unstable due to the ability of the recombinase to promote dissociation of the D-loop, a process referred to as the D-loop cycle.…”

Section: Pol IV Is Error-prone At D-loopsmentioning

confidence: 99%

DNA polymerases are error-prone at RecA-mediated recombination intermediates

2013

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G enetic studies have suggested thatY-family translesion DNA polymerase IV (DinB) performs error-prone recombination-directed replication (RDR) under conditions of stress due to its ability to promote mutations during double-strand break (DSB) repair in growth-limited E. coli cells. In recent studies we have demonstrated that pol IV is preferentially recruited to D-loop recombination intermediates at stressinduced concentrations and is highly mutagenic during RDR in vitro. These findings verify longstanding genetic data that have implicated pol IV in promoting stress-induced mutagenesis at D-loops. In this Extra View, we demonstrate the surprising finding that A-family pol I, which normally exhibits high-fidelity DNA synthesis, is highly error-prone at D-loops like pol IV. These findings indicate that DNA polymerases are intrinsically error-prone at RecA-mediated D-loops and suggest that auxiliary factors are necessary for suppressing mutations during RDR in non-stressed proliferating cells.

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UmuD and RecA Directly Modulate the Mutagenic Potential of the Y Family DNA Polymerase DinB

Cited by 104 publications

References 65 publications

Diverse responses to UV light exposure in Acinetobacter include the capacity for DNA damage-induced mutagenesis in the opportunistic pathogens Acinetobacter baumannii and Acinetobacter ursingii

Diverse responses to UV light exposure in Acinetobacter include the capacity for DNA damage-induced mutagenesis in the opportunistic pathogens Acinetobacter baumannii and Acinetobacter ursingii

RecA acts as a switch to regulate polymerase occupancy in a moving replication fork

DNA polymerases are error-prone at RecA-mediated recombination intermediates

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