UmuD2 Inhibits a Non-covalent Step during DinB-mediated Template Slippage on Homopolymeric Nucleotide Runs

Foti, James J.; DeLucia, Angela M.; Joyce, Catherine M.; Walker, Graham C.

doi:10.1074/jbc.m110.115774

Cited by 20 publications

(25 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.…”

supporting

confidence: 48%

“…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).…”

Section: Introductionmentioning

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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confidence: 48%

Section: Introductionmentioning

confidence: 99%

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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“…We conclude from the data presented here that Dpo4 uses a template slippage mechanism when making single-base deletion mutations in repetitive DNA sequences. Previous work on Dbh (6, 31) and E. coli DinB (10) indicates that they also use a template slippage mechanism. The archaeal and bacterial DinB polymerases, therefore, share a conserved mechanism when copying the kinds of repetitive sequences in which deletions most frequently occur.…”

Section: Discussionmentioning

confidence: 99%

“…Dbh has been shown to use a template slippage mechanism (6,31), while Dpo4 has been proposed to use dNTP-stabilized misalignment (9,12,16). Earlier experiments indicated that DinB from Escherichia coli used a dNTP-stabilized misalignment mechanism (28), although more recent work shows that it uses a template slippage mechanism (10). Human polymerase kappa can use a misinsertion-misalignment mechanism in nonrepetitive sequences, while template slippage has been inferred as the mechanism used in repetitive sequences (20,32).…”

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The Y-Family DNA Polymerase Dpo4 Uses a Template Slippage Mechanism To Create Single-Base Deletions

Wilson

Pata

2011

J Bacteriol

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The Y-family polymerases help cells tolerate DNA damage by performing translesion synthesis, yet they also can be highly error prone. One distinctive feature of the DinB class of Y-family polymerases is that they make single-base deletion errors at high frequencies in repetitive sequences, especially those that contain two or more identical pyrimidines with a 5 flanking guanosine. Intriguingly, different deletion mechanisms have been proposed, even for two archaeal DinB polymerases that share 54% sequence identity and originate from two strains of Sulfolobus. To reconcile these apparent differences, we have characterized Dpo4 from Sulfolobus solfataricus using the same biochemical and crystallographic approaches that we have used previously to characterize Dbh from Sulfolobus acidocaldarius. In contrast to previous suggestions that Dpo4 uses a deoxynucleoside triphosphate (dNTP)-stabilized misalignment mechanism when creating single-base deletions, we find that Dpo4 predominantly uses a template slippage deletion mechanism when replicating repetitive DNA sequences, as was previously shown for Dbh. Dpo4 stabilizes the skipped template base in an extrahelical conformation between the polymerase and the little-finger domains of the enzyme. This contrasts with Dbh, in which the extrahelical base is stabilized against the surface of the little-finger domain alone. Thus, despite sharing a common deletion mechanism, these closely related polymerases use different contacts with the substrate to accomplish the same result.The Y-family of DNA polymerases was defined in 2001 (21), following the discovery that the gene responsible for the variant form of xeroderma pigmentosum encodes polymerase (Pol) eta, the seventh human polymerase identified (19, 30). The major function of these polymerases is in the replication of damaged DNA by the process known as translesion synthesis (TLS). The TLS polymerases are thought to rescue stalled replicative polymerases, synthesizing short stretches of DNA before falling off and allowing replicative polymerases to continue. Y-family enzymes cluster into six groups. Of these, the DinB polymerases comprise the only group that is found in eukaryotes, bacteria, and the archaea.Like most other types of polymerases, the Y-family DNA polymerases have a structural architecture that consists of finger, palm, and thumb domains arranged to resemble a right hand. The topology of the palm domain, which contains the essential catalytic residues, places these enzymes into the "classical" polymerase superfamily (34). The relatively small sizes of the fingers and thumb domains, however, result in a spacious active site, which accounts for the high tolerance that the Y-family polymerases have for replicating damaged DNA bases and contributes to their low fidelity of DNA replication. All Y-family DNA polymerases possess a unique little-finger or polymerase-associated domain (LF/PAD) that is tethered to the polymerase thumb domain through a flexible polypeptide linker. The LF/PAD enhances DNA association by i...

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“…However, with the assistance of the β-clamp, the processivity of pol IV increases by 2-to 4-orders of magnitude enabling it to synthesize over 1 kb DNA (241). Recently, it has been suggested that UmuD physically interacts with Pol IV (85) and in doing so, helps cap the polymerase's active site, so as to increase pol IVs fidelity (71,85).…”

Section: Cofactor Requirements That Modify the Fidelity And Processivmentioning

confidence: 99%

Translesion DNA Synthesis

Vaisman¹,

McDonald²,

Woodgate³

2012

EcoSal

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All living organisms are continually exposed to agents that damage their DNA, which threatens the integrity of their genome. As a consequence, cells are equipped with a plethora of DNA repair enzymes to remove the damaged DNA. Unfortunately, situations nevertheless arise where lesions persist, and these lesions block the progression of the cell's replicase. Under these situations, cells are forced to choose between recombination-mediated "damage avoidance" pathways, or use a specialized DNA polymerase (pol) to traverse the blocking lesion. The latter process is referred to as Translesion DNA Synthesis (TLS). As inferred by its name, TLS not only results in bases being (mis)incorporated opposite DNA lesions, but also downstream of the replicase-blocking lesion, so as to ensure continued genome duplication and cell survival. Escherichia coli and Salmonella typhimurium possess five DNA polymerases, and while all have been shown to facilitate TLS under certain experimental conditions, it is clear that the LexA-regulated and damage-inducible pols II, IV and V perform the vast majority of TLS under physiological conditions. Pol V can traverse a wide range of DNA lesions and performs the bulk of mutagenic TLS, whereas pol II and pol IV appear to be more specialized TLS polymerases. KeywordsDNA polymerase II; DNA polymerase IV; DNA polymerase V; RecA, LexA, β-clamp; Y-family DNA polymerase; Mutagenesis; Replication Restart; Recombination; SOS response HISTORICAL OVERVIEWWe now know that TLS is largely facilitated by specialized DNA polymerases that can accommodate bulky adducts in their active sites. Such properties are usually associated with a dramatic decrease in replication fidelity and as a consequence, TLS is often error-prone, leading to an increase in cellular mutagenesis. Significant progress in understanding the FURTHER READINGFor additional recent reviews on TLS-related topics see references (6,76,101,122,167,173,179,180,203,214). HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript molecular mechanisms of TLS have been achieved in the past decade, following the successful purification and biochemical characterization of a number of TLS polymerases. However, prior to the characterization of the highly purified proteins, the pioneering studies on TLS were largely focused on its genetic endpoints, namely its mutagenic consequences. Indeed, the first hint that damage-induced mutagenesis is not a passive process came in the early '50s when Jean Weigle reported that mutagenesis of irradiated bacteriophage λ was significantly enhanced, if the host bacterium had also been irradiated (247). However, it was not until the pioneering studies of Evelyn Witkin working with bacteria that could be killed by UV irradiation, but not mutated, that the concept of damage inducible error-prone translesion DNA synthesis was born (249)(250)(251)253). These ideas were further expanded in 1970 by Miroslav Radman in a privately circulated letter in which he suggested that "SOS replication" ...

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UmuD2 Inhibits a Non-covalent Step during DinB-mediated Template Slippage on Homopolymeric Nucleotide Runs

Cited by 20 publications

References 40 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

The Y-Family DNA Polymerase Dpo4 Uses a Template Slippage Mechanism To Create Single-Base Deletions

Translesion DNA Synthesis

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