Proficient and Accurate Bypass of Persistent DNA Lesions by DinB ...

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Feb 23, 2007 - at the N2 position of dG, nitrofurazone (NFZ) and 4-nitroquinoline. 1-oxide (4-NQO), has allowed us to determine whether dinB clearly falls into ...
[Cell Cycle 6:7, 817-822, 1 April 2007]; ©2007 Landes Bioscience

Perspective

Proficient and Accurate Bypass of Persistent DNA Lesions by DinB DNA Polymerases Daniel F. Jarosz1 Veronica G. Godoy2 Graham C. Walker3,*

Abstract

2Department of Biology; Northeastern University; Boston, Massachusetts USA

*Correspondence to: Graham C. Walker; Department of Biology; 68-633, 77 Massachusetts Ave.; Cambridge, Massachusetts 02139 USA; Tel.: 617.253.6716; Fax: 617.253.2643. Email: [email protected]

DinB, polymerase, DNA damage, pol k, XPV, mutagenesis Acknowledgements

DNA damage from both exogenous and endogenous sources is a difficulty with which all organisms must contend. Both the frequency and chemical diversity of such damage is considerable.1 For example, it is estimated that nearly 10,000 abasic sites are spontaneously generated in a single eukaryotic cell each day.2 Due to the universality of this problem, DNA repair pathways have been conserved throughout evolution (Fig. 1).1 In addition, several alternative approaches, collectively termed DNA damage tolerance pathways because they do not remove DNA damage, have also been evolutionarily conserved.1 One such mechanism, translesion synthesis (TLS), plays a crucial role in the DNA damage response of organisms from bacteria to humans.3,4 In TLS, specialized DNA polymerases incorporate a deoxyribonucleotide opposite to an otherwise replication‑blocking DNA lesion and continue DNA synthesis past the site of damage (Fig. 1). The majority of these enzymes belong to the Y‑family of DNA polymerases, various subfamilies of which are found throughout evolution.5 The consequence of their broadened substrate specificity, however, is relaxed fidelity relative to replicative polymerases.4 Therefore regulation of Y‑family polymerases is essential for the maintenance of genomic integrity. Indeed, Y‑family polymerases are responsible for both spontaneous and induced mutagenesis in many organisms.1,4,6,7 The function of the only individual Y‑family polymerase conserved among all three domains of life, DinB/pol k (Fig. 2), has recently been elucidated.8‑12 Although identified in the first functional screen for transcripts upregulated upon DNA damage in Escherichia coli,13 an absence of striking and genetically tractable phenotypes, particularly relative to its homologs, resulted in comparatively few insights into DinB function. Here we will summarize the data regarding DinB/pol k dependent mutagenesis and propose a revised view of its function as a specialized DNA polymerase with mutagenic potential that arises along with its unique substrate specificity.

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We are also grateful to members of the Walker laboratory for comments on the manuscript. G.C.W. is an American Cancer Society Research Professor. Funding was provided by National Institutes of Health grant CA021615 to G.C.W. and NIEHS grant P30 ES002109 to the MIT Center for Environmental Health Sciences.

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1Department of Chemistry; 3Department of Biology; Massachusetts Institute of Technology; Cambridge, Massachusetts USA

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Despite nearly universal conservation through evolution, the precise function of the DinB/pol k branch of the Y‑family of DNA polymerases has remained unclear. Recent results suggest that DinB orthologs from all domains of life proficiently bypass replica‑ tion blocking lesions that may be recalcitrant to DNA repair mechanisms. Like other translesion DNA polymerases, the error frequency of DinB and its orthologs is higher than the DNA polymerases that replicate the majority of the genome. However, recent results suggest that some Y‑family polymerases, including DinB and pol k, bypass certain types of DNA damage with greater proficiency than an undamaged template. Moreover, they do so relatively accurately. The ability to employ this mechanism to manage DNA damage may be especially important for types of DNA modification that elude repair mechanisms. For these lesions, translesion synthesis may represent a more important line of defense than for other types of DNA damage that are more easily dealt with by other more accurate mechanisms.

Untargeted, Spontaneous and Induced Mutagenesis The dinB gene was identified in a functional screen for genes that are transcriptionally upregulated following DNA damage in E. coli.13 Unlike its homolog umuC, however, deletion of dinB does not confer striking phenotypes with respect to spontaneous and induced mutagenesis or sensitivity to many DNA damaging agents. Subsequent studies www.landesbioscience.com

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at a possible direct role in DNA synthesis.23 Previous models had suggested that these gene products might interact with replicative polymerases, thereby modulating their fidelity.1 The subsequent findings that Rad30/XP‑V, DinB, and UmuD′2C are also DNA polymerases led to the discovery of a new superfamily of DNA polymerases, the Y‑family.8,24‑27 These polymerases participate in TLS and are characterized by their comparatively low fidelity on undamaged DNA.4 The need for DNA polymerases to be highly regulated is evident from the large number of DNA polymerases present in many Figure 1. Cellular responses to DNA damage, including DNA damage tolerance organisms—e.g., 5 in E. coli, 10 in S. cerervisiae, and 16 in via translesion synthesis. If an unrepaired lesion (shown in red) remains in the chro‑ H. sapiens—with error rates varying over many orders of mosome during replication, it may be bypassed by translesion synthesis in which magnitude.1 a specialized polymerase (shown in green) is recruited to the replication fork and Like other Y‑family polymerases, DinB and its orthologs copies over the lesion. appear to act with a range of error frequencies on damaged and undamaged templates. DinB from E. coli synthesizes undamestablished a role for dinB in two enigmatic mutagenic phenomena— aged and certain damaged templates with error frequencies between l untargeted mutagenesis (UTM)7 and adaptive mutagenesis.9,14 In 10‑3 and 10‑5,11,28 while the mammalian ortholog synthesizes undamUTM, UV‑irradiated E. coli are transfected with non-irradiated l aged DNA with a slightly higher error frequency of 10‑2‑10‑3.29 Both phage. Strikingly, the untargeted mutagenesis subsequently observed enzymes also have the ability to produce ‑1 frameshift mutations in l is dependent both on the UV‑dose administered and the E. coli during DNA synthesis at an appreciable frequency.8,28,29 Despite genes dinB and recA. The dependence on UV‑irradiation is unrelated these error frequencies, certain data suggest that DinB/pol k function to induction of the SOS DNA damage response, as the dependence is may in fact be antimutagenic in vivo. Although deletion of either still observed in constitutively SOS‑activated lexA mutant.7 Analysis gene does not alter the frequency of spontaneous mutation,7,17 it of the spectrum of mutations reveals a distribution between ‑1 frame- results in an increase in the frequency of mutagenesis induced by shift events and base substitutions with a preference for the sequence certain DNA damaging agents.11,20 Such behavior is analogously context 5‑GX‑3.15 observed with respect to UV‑induced mutation in human cells defiIn E. coli, deletion of the dinB gene does not have a profound cient in pol h function, which replicates relatively accurately over effect on either spontaneous or induced mutagenesis.1 Moderate over- thymine‑thymine cyclobutane dimers.30,31 Substrate specificity also expression of DinB does promote a variety of mutagenic phenomena, appears to be conserved between DinB and pol k. Both enzymes are however. Spontaneous mutagenesis induced by overexpression of able to bypass N2-B[a]P-adducted template G.20,32,33 Moreover, they DinB exhibits a strong preference for ‑1 frameshift mutations, but each display a striking 10‑15 fold increased activity on a template also a substantial increase in certain base substitution mutations at N2‑furfuryl‑dG relative to undamaged DNA.11 Increased profipurines.16 Moreover, treatment with 4‑NQO dramatically increases ciency is also displayed by pol h replicating its cognate substrate T‑T the frequency of ‑1 frameshift mutations observed. Despite the cyclobutane pyrimidine dimers.34 Curiously, both DinB and pol k relative ambiguity of these phenomena, they laid the foundation, proficiently extend from a variety of lesions and mismatched primer particularly in concert with the known mutagenic phenotypes of the ends in addition to their insertion specificities.8,11,35‑39 It has been dinB homolog umuC, for a view of dinB as an agent of mutation. suggested, at least for pol k, that this property reflects a separate role Eukaryotic pol k also participates in a variety of mutagenic in the extension step of TLS.35 phenomena.17 Although pol k‑/‑ mice are viable and fertile, they display a mutator phenotype.18 Pol k‑/‑ mouse embryonic fibroblasts Adaptive Mutagenesis are sensitive to benzo[a]pyrene19 and are impaired in replicating a The report of adaptive mutation under conditions of nonlethal gapped plasmid containing a site‑specific N2‑B[a]P‑dG lesion.20 Pol k‑/‑ mice also show increased spontaneous mutagenesis18 and pol selection challenged the prevailing notion established by Luria and k appears to play a role in recovery from a B[a]P‑induced S‑phase Delbruck that mutants arise spontaneously during growth and are 40 checkpoint.21 Similarly to E. coli DinB, overproduction of pol k preexisting at the time of selection. In the case of adaptive mutation, stationary phase E. coli that are unable to metabolize lactose not only increases mutation frequency but also promotes double by virtue of a +1 frameshift in an episomal fused lacI‑lacZ allele are strand breaks (DSB), increased homologous recombination and plated on medium with lactose as the sole carbon source.14 New lac+ nonhomologous end joining, loss of heterozygosity (LOH), and aneuploidy.22 The striking panel of genetic abnormalities induced mutants appear over time despite the fact that the bacteria are not by improper expression of pol k clearly indicates the importance of growing. The molecular details of the mechanism responsible for this regulating potentially mutagenic Y‑family polymerases in multicel- mutagenesis are quite controversial, but the involvement of dinB is well‑established.41‑49 lular organisms. The fact that deletion of the chromosomal dinB gene does not profoundly alter spontaneous mutagenesis suggests that DinB funcLesion Bypass Polymerases: A New Enzyme Superfamily tion may not always be mutagenic. Indeed, it has been suggested that Despite the known function of dinB and its eukaryotic and the ‑1 frameshift phenotype observed in adaptive mutagenesis arises prokaryotic homologs in mutagenesis, its mechanism remained as a consequence of its substrate specificity50 and the increased levels poorly understood for many years. The discovery that REV1 from of DinB produced from the episomal copy.49 DNA pol k has not Saccharomyces cerevisiae encodes a dCMP transferase activity hinted been shown to participate in a phenomenon such as adaptive muta818

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These in vivo observations stimulated in vitro studies which led to the discovery that E. coli DinB is able to bypass an adduct produced by NFZ with 15‑fold greater efficiency than undamaged DNA. This property appears to be shared by DinB orthologs from archaea and mammals. Moreover, bypass is relatively accurate with misinsertion frequencies varying between 10‑3 and 10‑5. The observation that deletion of dinB strongly affects killing by NFZ but does not alter mutation frequency suggests that the accuracy of DinB mediated lesion bypass is comparable to that of other cellular processes that act in DNA repair and damage tolerance. When we generated a model of DinB encountering a DNA lesion produced by nitrofurazone (Fig. 3A and B), we noted that a pocket in the enzyme is appropriately positioned to accommodate an N2 modification on a template dG, bringing the adduct into contact with the ‘steric gate’ of DinB (F13). In DNA polymerases, ‘steric gates’ are responsible for the occlusion of improper rNTP substrates Figure 2. Conservation of DinB/Pol κ through evolution. (A) All DinB orthologs possess a central Y-fam‑ from the growing DNA chain, but we ily polymerase catalytic domain (shown in green). This is elaborated in eukaryotes with extended Nwondered whether this contact might also terminal regions and often with C-terminal zinc finger domains (shown in blue), which have been shown provide a basis for increased activity on to bind ubiquitin.65 (B) Phylogeny of DinB/Pol κ sequences from all domains of life. Sequences from 2 most prokaryotes and some eukaryotes (shaded in orange) consist primarily of the central polymerase an N ‑dG adducted template (Fig. 3B). Strikingly, mutation of F13 to V13 renders domain, whereas those from certain other eukaryotes such as C. elegans show extended N- and C-ter‑ minal regions. Higher eukaryotic Pol κ sequences contain both an extended N-terminal region and a DinB virtually inactive for TLS but does not C-terminus with two zinc-finger domains that has been shown to bind ubiquitin. reduce its polymerase activity on undamaged templates.11 Moreover, the mutant is tion, but its mutational signature when overproduced does include ‑1 unable to complement nitrofurazone and 4‑NQO sensitivity, indiframeshift events.17 Structural analysis of the archaeal DinB homo- cating that lesion bypass is required for resistance to these agents in logs Dbh and Dpo4 indicate that the active site of DinB may be able vivo. It is provocative that throughout evolution no DinB orthologs to accommodate more than one nucleotide as a consequence of their possess a non-aromatic residue at this position. specialized bypass ability, thereby permitting a template bulge that Given the multiple and redundant high fidelity DNA repair and would give rise to a ‑1 frameshift mutation.51,52 tolerance pathways available to the cell, why employ potentially mutagenic TLS? An emerging body of evidence suggests that certain types of DNA damage, particularly modification at the N2 position Sloppier Copiers or Specialized Polymerases? of dG, may be particularly recalcitrant to such repair pathways. In The notion that Y‑family polymerases always act as low fidelity mammalian cells damaged with acetylaminofluorine, the N2‑dG polymerases is inconsistent with the fact that XP‑V patients, who isomer is the most persistent lesion observed despite being the least bear mutant Rad30/pol h alleles, are prone to skin and other cancers commonly produced.55 Moreover, certain other N2‑dG adducts suggesting that the function of pol h may be antimutagenic in have been shown to be recalcitrant to repair by the E. coli nucleotide humans.25,53 XP‑V cells in culture also show increased UV‑induced excision repair system in vitro.56 These observations are particularly mutagenesis.30 This is in striking contrast to other mammalian interesting given the recent finding that pol k may play a role in Y‑family polymerases such as Rev1, whose action generates clear nucleotide excision repair in mammalian cells.12 mutagenic signatures.23,54 Our recent discovery of the sensitivity of a DdinB strain to two DNA damaging agents that produce adducts Sliding Clamps, Ubiquitination and Other at the N2 position of dG, nitrofurazone (NFZ) and 4‑nitroquinoline Posttranslational Regulatory Mechanisms 1‑oxide (4‑NQO), has allowed us to determine whether dinB clearly 11 falls into one of these categories. DinB catalytic function is clearly Although a number of recent studies have clearly shown that TLS required for resistance to these agents, but deletion strains show can occur with appreciable fidelity, by and large TLS is a poteneither the same or increased induced mutation frequency relative to tially mutagenic strategy for coping with DNA damage. A growing the wild‑type when treated with either agent.11 These observations, body of evidence suggests that access of Y‑family polymerases to the taken together with the fact that a chromosomal deletion does not replication fork is therefore restricted in some fashion to prevent alter either spontaneous or induced mutagenesis suggest that dinB is spurious mutagenesis. The mechanisms that permit a Y‑family DNA largely anti‑mutagenic under many circumstances. polymerase to access a primer terminus in prokaryotes are relatively www.landesbioscience.com

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Conclusions and Future Questions

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Although initially considered agents of mutation, recent developments have led to the more nuanced view that the relative infidelity of Y‑family polymerases results from their broadened substrate specificity. Indeed, the potential for base substitution or even frameshift mutagenesis may be far preferable to the risk of chromosomal rearrangements induced by stalled replication forks ‑ particularly in higher eukaryotes where most of the genome is non-coding. However, several key questions regarding regulation remain. In the case of DinB/pol k branch of the superfamily, TLS may be particularly important because its apparent cognate substrates appear to be recalcitrant to other repair mechanisms.55,56 However, other TLS polymerases act on lesions that can be efficiently and accurately repaired by any number of other mechanisms. Further studies will be required to elucidate what dictates the choice of TLS over other DNA repair and damage tolerance mechanisms. It is still unclear what regulates access to the replication fork, presumably preventing these potentially mutagenic enzymes from inappropriately compromising genomic integrity. Moreover, whether selection of the proper polymerase occurs merely by stochastic competition or by more a more orchestrated mechanism is a topic of intense debate.62,66,68,69 Another key question is whether TLS occurs solely at static stalled replication forks or perhaps additionally at gaps left after replication reinitiation. Recent results in S. cerevisiae have suggested that replication blocking lesions can induce both leading and lagging strand gaps,70 evoking early models of replication in E. coli.71 Although it is clear that regression of stalled replication forks also plays an important role in TLS,72 these observations have led to the speculation that TLS polymerases may act post‑replicatively at such gaps.73 Such a model is supported by the recent observation that in S. cerevisiae the Y‑family member Rev1 is most highly expressed not in S‑phase but rather in G2/M, after the majority of DNA replication has taken place.73 This model is also particularly attractive given the weak activity of Y‑family DNA polymerases, as it allows replication and TLS to be carried out in parallel rather than in series.74 Further research will give considerable insight into these and other problems.

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Figure 3: Model of an incipient (A) G:C basepair and (B) an N2-furfuryl-G: C basepair in the active site of E. coli DinB. Template G or an N2-furfuryl-G is shown in green, incoming C is shown in yellow, the ‘steric gate’ residue is shown in red, and the primer terminus is shown in blue.

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poorly understood although both UmuD'2C and DinB require an interaction with b, the prokaryotic processivity clamp, for their in vivo function. Furthermore, in E. coli, much of the DNA damage response is temporally controlled by the facilitated autoproteolysis of UmuD to UmuD.57 UmuD2 interacts with the b processivity clamp with greater affinity than UmuD'2 while UmuD'2 interacts with the catalytic subunit of the replicative polymerase (DNA pol III) better than UmuD2,58 leading to the speculation that these interactions may regulate the timing and location TLS.59 In eukaryotes it has recently been discovered that posttranslational modification of the PCNA processivity clamp by ubiquitination is required for TLS in vivo.60‑63 Furthermore, interaction with PCNA is a requirement for focus formation of pol k in response to DNA damage.64 The alternative processivity clamp Rad9‑Rad1‑Hus1 (9‑1‑1) has been also shown to be important for DinB function in Schizosaccharomyces pombe.65 The role of ubiquitin in TLS is even more elaborate than simple PCNA modification. It has recently been shown that eukaryotic TLS polymerases bind ubiquitin and are themselves subject to ubiquitination.66,67 Such modification appears to be important for their function in mutagenesis and in prevention of lethality induced by various DNA damaging agents. The regulation of TLS polymerases has clear implications for cancer, as many XP‑V patients bear versions of Rad30 that are in principle competent for translesion synthesis but are lacking one or more putative regulatory domains.53 The scope of posttranslational modification in regulating TLS is likely to be considerable. 820

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