DNA Damage Control by Novel DNA Polymerases: Translesion Replication and Mutagenesis

single-stranded DNA double-stranded DNA translesion replication polymerase cyclobutyl pyrimidine dimer adenosine 5′-3-O- (thio)triphosphate DNA is constantly subjected to injuries inflicted by external agents such as UV light or cigarette smoke, by intracellular by-products of metabolism such as reactive oxygen species, or by spontaneous decay. DNA lesions interfere with replication and with transcription and if left in DNA can cause mutation, malfunction, and cell death. These deleterious effects are usually prevented by DNA repair mechanisms, which remove the damaged nucleotide and restore the original DNA sequence (for review, see Ref.1Friedberg E.C. Walker G.C. Siede W. DNA Repair and Mutagenesis. ASM Press, Washington, D. C.1995Google Scholar). However, the repair mechanisms are not fully efficient, and some lesions persist in the DNA. The attempt to replicate such unrepaired lesions usually leads to an interruption of replication and to the formation of a ssDNA1 region carrying the damaged nucleotide, a gap-lesion structure. Filling in of gap-lesion structures can be done by one of two known mechanisms: recombinational repair and translesion replication. Recombinational repair consists of patching the gap with a DNA segment that was cut out from the undamaged strand in the fully replicated sister chromatid (2Kowalczykowski S.C. Dixon D.A. Eggleston A.K. Lauder S.D. Rehrauer W.M. Microbiol. Rev. 1994; 58: 401-465Crossref PubMed Google Scholar, 3Cox M.M. Prog. Nucleic Acids Res. Mol. Biol. 1999; 63: 311-366Crossref PubMed Google Scholar). This converts the damaged region into the dsDNA form, enabling a second attempt of error-free repair. Alternatively, the gap may be filled in by DNA synthesis, a process that is inherently mutagenic because of the miscoding nature of most damaged nucleotides. This pathway was, therefore, termed translesion replication (TLR 2We prefer the term translesion replication over translesion synthesis because the former clearly implies a DNA reaction.), translesion synthesis, error-prone repair, mutagenic repair, bypass synthesis, or lesion bypass (4Strauss B.S. Cancer Surv. 1985; 4: 493-516PubMed Google Scholar, 5Echols H. Goodman M.F. Annu. Rev. Biochem. 1991; 60: 477-511Crossref PubMed Scopus (624) Google Scholar, 6Livneh Z. Cohen-Fix O. Skaliter R. Elizur T. CRC Crit. Rev. Biochem. Mol. Biol. 1993; 28: 465-513Crossref PubMed Scopus (104) Google Scholar). A third mechanism that may exist was termed copy choice replication, but only little is known about it (7Higgins N.P. Kato K. Strauss B. J. Mol. Biol. 1976; 101: 417-425Crossref PubMed Scopus (362) Google Scholar, 8Koffel-Schwartz N. Coin F. Veaute X. Fuchs R.P.P. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7805-7810Crossref PubMed Scopus (61) Google Scholar, 9Nikolaishvili-Feinberg N. Cordeiro-Stone M. J. Biol. Chem. 2000; 275: 30943-30950Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). In the last 2 years a major breakthrough has occurred with the discovery that TLR is carried out by specialized DNA polymerases that belong to a novel superfamily. These DNA polymerases, which were found in a number of organisms ranging from Escherichia coli to humans, exhibit a high frequency of errors during in vitroDNA synthesis. Some of them clearly function in TLR, whereas the functions of others are unknown yet (for recent reviews, see Refs.10Johnson R.E. Washington M.T. Prakash S. Prakash L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12224-12226Crossref PubMed Scopus (131) Google Scholar, 11Woodgate R. Genes Dev. 1999; 13: 2191-2195Crossref PubMed Scopus (234) Google Scholar, 12Goodman M.F. Trends Biochem. Sci. 2000; 25: 189-195Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 13Hubscher U. Nasheuer H.P. Syvaoja J.E. Trends Biochem. Sci. 2000; 25: 143-147Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 14Friedberg E.C. Feaver W.J. Gerlach V.L. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 5681-5683Crossref PubMed Scopus (226) Google Scholar). This review will present an overview of the new DNA polymerases, focus on E. coli DNA polymerase V and human DNA polymerase η, and conclude with a discussion of some general issues in TLR. In E. coli TLR is regulated by the SOS response. The main component of this reaction is one of the novel DNA polymerases, a product of the umuC gene termed pol V (15Tang M. Shen X. Frank E.G. O'Donnell M. Woodgate R. Goodman M.F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8919-8924Crossref PubMed Scopus (488) Google Scholar, 16Reuven N.B. Arad G. Maor-Shoshani A. Livneh Z. J. Biol. Chem. 1999; 274: 31763-31766Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar). 3We term the umuC gene product pol V, whereas Goodman and colleagues (15Tang M. Shen X. Frank E.G. O'Donnell M. Woodgate R. Goodman M.F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8919-8924Crossref PubMed Scopus (488) Google Scholar) term the complex of UmuD′2C pol V. Until the role of UmuD′ is clearly defined, we prefer to call UmuC pol V. TheumuC gene is a typical SOS gene, which is repressed by LexA and induced by RecA (for a review on the SOS system see Ref. 1Friedberg E.C. Walker G.C. Siede W. DNA Repair and Mutagenesis. ASM Press, Washington, D. C.1995Google Scholar). The lesion bypass activity of pol V requires three additional proteins: UmuD′, a shorter form of UmuD formed by RecA-mediated proteolysis (17Walker G.C. Trends Biochem. Sci. 1995; 20: 416-420Abstract Full Text PDF PubMed Scopus (93) Google Scholar), RecA, and SSB (15Tang M. Shen X. Frank E.G. O'Donnell M. Woodgate R. Goodman M.F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8919-8924Crossref PubMed Scopus (488) Google Scholar, 16Reuven N.B. Arad G. Maor-Shoshani A. Livneh Z. J. Biol. Chem. 1999; 274: 31763-31766Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar). In addition, it is stimulated by the processivity subunits of pol III, namely the β subunit sliding clamp and the γ complex clamp loader (15Tang M. Shen X. Frank E.G. O'Donnell M. Woodgate R. Goodman M.F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8919-8924Crossref PubMed Scopus (488) Google Scholar). Based on genetic evidence pol V is the main lesion bypass polymerase in E. coli. Inactivating TLR by a umuC mutation leads to a modest reduction in resistance to DNA-damaging agents such as UV light, suggesting that TLR has a small contribution to survival or DNA repair. On the other hand, the umuC mutation strongly decreases mutagenesis by DNA-damaging agents, implying that most of the mutations are caused by pol V-dependent TLR (1Friedberg E.C. Walker G.C. Siede W. DNA Repair and Mutagenesis. ASM Press, Washington, D. C.1995Google Scholar, 17Walker G.C. Trends Biochem. Sci. 1995; 20: 416-420Abstract Full Text PDF PubMed Scopus (93) Google Scholar). E. coli contains another member of the new DNA polymerase family, pol IV, the product of the dinB gene. pol IV is a low fidelity DNA polymerase (18Wagner J. Gruz P. Kim S.R. Yamada M. Matsui K. Fuchs R.P.P. Nohmi T. Mol. Cell. 1999; 4: 281-286Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar), which is responsible for a special branch of mutagenesis observed in unirradiated phage λ when it infects an irradiated E. coli host (19Brotcorne-Lannoye A. Maenhaut-Michel G. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 3904-3908Crossref PubMed Scopus (118) Google Scholar). Acting in this pathway or when overproduced in E. coli cells, pol IV leads to the preferential production of frameshift mutations (20Wood R.D. Hutchinson F. J. Mol. Biol. 1984; 173: 293-305Crossref PubMed Scopus (61) Google Scholar, 21Kim S.R. Maenhaut-Michel G. Yamada M. Yamamoto Y. Matsui K. Sofuni T. Nohmi T. Ohmori H. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 13792-13797Crossref PubMed Scopus (296) Google Scholar, 22Wagner J. Nohmi T. J. Bacteriol. 2000; 182: 4587-4595Crossref PubMed Scopus (135) Google Scholar). It was suggested that pol IV can perform lesion bypass in vivo, at least in specific cases (23Napolitano R. Janel-Bintz R. Wagner J. Fuchs R.P.P. EMBO J. 2000; 19: 6259-6265Crossref PubMed Scopus (330) Google Scholar), and that it is involved in spontaneous mutagenesis (24Strauss B.S. Roberts R. Francis L. Pouryazdanparast P. J. Bacteriol. 2000; 182: 6742-6750Crossref PubMed Scopus (74) Google Scholar); however, its full biological role is not clear. Remarkably, homologs of umuC are carried on natural conjugative plasmids present in bacteria (25Woodgate R. Sedgwick S.G. Mol. Microbiol. 1992; 6: 2213-2218Crossref PubMed Scopus (91) Google Scholar). These plasmids often carry multiple antibiotic resistance genes and are responsible, in part, for the growing problem of resistance toward antibiotics among bacterial pathogens (26Davies J. Science. 1994; 264: 375-382Crossref PubMed Scopus (1455) Google Scholar). One of these homologs, mucB, is present in plasmid R46 and in its derivative pKM101, which is used to increase the sensitivity of the Salmonella Ames test for mutagens (27McCann J. Spingarn N.E. Kobori J. Ames B.N. Proc. Natl. Acad. Sci. U. S. A. 1975; 72: 979-983Crossref PubMed Scopus (969) Google Scholar). MucB was shown to be pol RI, a DNA polymerase specialized for lesion bypass (28Goldsmith M. Sarov-Blat L. Livneh Z. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 11227-11231Crossref PubMed Scopus (47) Google Scholar). Like pol V, the bypass activity of pol RI requires also the plasmid-encoded MucA′ protein (homolog of UmuD′) and the host RecA and SSB proteins. An intriguing possibility is that these mutation-producing (mutase) polymerases have a role in the phenomenon of antibiotics resistance among bacterial pathogens (28Goldsmith M. Sarov-Blat L. Livneh Z. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 11227-11231Crossref PubMed Scopus (47) Google Scholar). The yeast Saccharomyces cerevisiae contains two TLR systems: the pol ζ (REV) system and the pol η (RAD30) system. The REV system contains three genes:REV1, REV3, and REV7 (29Lawrence C.W. Hinkle D.C. Cancer Surv. 1996; 28: 21-31PubMed Google Scholar).REV3 encodes the DNA polymerase subunit, which together withREV7 forms pol ζ (30Nelson J.R. Lawrence C.W. Hinkle D.C. Science. 1996; 272: 1646-1649Crossref PubMed Scopus (603) Google Scholar). Interestingly, pol ζ, is similar to the “classical” pol δ rather than to UmuC. In vitro, pol ζ was shown to bypass a thymine-thymine cyclobutyl pyrimidine dimer (CPD), although with moderate efficiency (30Nelson J.R. Lawrence C.W. Hinkle D.C. Science. 1996; 272: 1646-1649Crossref PubMed Scopus (603) Google Scholar). In addition, pol ζ was shown to extend mismatches with high efficiency, including nucleotides inserted opposite a lesion (31Johnson R.E. Washington M.T. Haracska L. Prakash S. Prakash L. Nature. 2000; 406: 1015-1019Crossref PubMed Scopus (585) Google Scholar). REV1 is similar to the E. coli UmuC; however, it has dCMP transferase activity rather than DNA polymerase activity (32Nelson J.R. Lawrence C.W. Hinkle D.C. Nature. 1996; 382: 729-731Crossref PubMed Scopus (510) Google Scholar). Inactivation of theREV system causes mild or no UV sensitivity, but it greatly reduces UV mutagenesis, indicating that pol ζ is important in TLR inS. cerevisiae (29Lawrence C.W. Hinkle D.C. Cancer Surv. 1996; 28: 21-31PubMed Google Scholar). In addition, S. cerevisiaecontains an additional homolog of umuC, termedRAD30. This gene encodes pol η, a DNA polymerase that is specialized for replicating certain lesions. Most remarkably, pol η replicates a thymine-thymine CPD with the same efficiency and the same accuracy as it replicates a non-damaged thymine-thymine sequence (33Johnson R.E. Prakash S. Prakash L. Science. 1999; 283: 1001-1004Crossref PubMed Scopus (699) Google Scholar). pol η provides the paradigm for the new phenomenon of non-mutagenic, relatively error-free bypass of DNA lesions. No homolog ofdinB was found in S. cerevisiae. Human cells contain TLR systems similar to the S. cerevisiaepol ζ and pol η ones and two additional novel DNA polymerases similar to pol η. Humans contain homologs of the yeastREV3 (34Gibbs P.E. McGregor W.G. Maher V.M. Nisson P. Lawrence C.W. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6876-6880Crossref PubMed Scopus (296) Google Scholar) and REV7 (35Murakumo Y. Roth T. Ishii H. Rasio D. Numata S. Croce C.M. Fishel R. J. Biol. Chem. 2000; 275: 4391-4397Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar) genes and are therefore likely to have pol ζ, although this was not yet proven biochemically. Humans contain also a homolog of REV1, which was reported to have dCMP transferase activity (36Lin W. Xin H. Zhang Y. Wu X. Yuan F. Wang Z. Nucleic Acids Res. 1999; 27: 4468-4475Crossref PubMed Scopus (167) Google Scholar), similar to the yeast enzyme.In vivo experiments with human cultured cells have shown that decreasing the expression of REV3 (34Gibbs P.E. McGregor W.G. Maher V.M. Nisson P. Lawrence C.W. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6876-6880Crossref PubMed Scopus (296) Google Scholar) or ofREV1 (37Gibbs P.E. Wang X.D. Li Z. McManus T.P. McGregor W.G. Lawrence C.W. Maher V.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4186-4191Crossref PubMed Scopus (163) Google Scholar) with antisense RNA led to a reduction in UV mutagenesis, suggesting a major role for the REV system in TLR. Interestingly, the attempts to knock-out REV3 in mice led to embryonic lethality, and no cell line could be established from these embryos (38Bemark M. Khamlichi A.A. Davies S.L. Neuberger M.S. Curr. Biol. 2000; 10: 1213-1216Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 39Wittschieben J. Shivji M.K. Lalani E. Jacobs M.A. Marini F. Gearhart P.J. Rosewell I. Stamp G. Wood R.D. Curr. Biol. 2000; 10: 1217-1220Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 40Esposito G. Godindagger I. Klein U. Yaspo M.L. Cumano A. Rajewsky K. Curr. Biol. 2000; 10: 1221-1224Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). This indicates a vital role for pol ζ and possibly for TLR in mammals. Similar to S. cerevisiae, humans contain a TLR system based on pol η. pol η is encoded by the XP-V gene (41Masutani C. Kusumoto R. Yamada A. Dohmae N. Yokoi M. Yuasa M. Araki M. Iwai S. Takio K. Hanaoka F. Nature. 1999; 399: 700-704Crossref PubMed Scopus (1161) Google Scholar, 42Johnson R.E. Kondratick C.M. Prakash S. Prakash L. Science. 1999; 285: 263-265Crossref PubMed Scopus (675) Google Scholar), which is mutated in the variant form of the genetic disease xeroderma pigmentosum (XP; the other forms of the disease are caused by mutations in error-free nucleotide excision repair). This disease is characterized by sun sensitivity and cancer predisposition, and cell lines established from XP-V patients exhibit hypermutability by and sensitivity to UV radiation (1Friedberg E.C. Walker G.C. Siede W. DNA Repair and Mutagenesis. ASM Press, Washington, D. C.1995Google Scholar, 43Cordonnier A.M. Fuchs R.P. Mutat. Res. 1999; 435: 111-119Crossref PubMed Scopus (99) Google Scholar). Thus, although pol η-dependent TLR is not essential in humans, it does act as a major anti-mutagenic and therefore anti-cancer mechanism. This provides the most convincing example that TLR may be functionally non-mutagenic under certain biologically important circumstances. Humans contain two additional homologs of umuC:hRAD30B, encoding DNA polymerase ι (44Tissier A. McDonald J.P. Frank E.G. Woodgate R. Genes Dev. 2000; 14: 1642-1650PubMed Google Scholar, 45Zhang Y. Yuan F. Wu X. Wang Z. Mol. Cell. Biol. 2000; 20: 7099-7108Crossref PubMed Scopus (189) Google Scholar), andhDINB1, encoding pol κ (termed also pol θ) 4The multiplicity of new DNA polymerases and their discovery within a short period of time caused a confusion in nomenclature. The protein encoded by hDINB1 was termed pol θ by one group (46Johnson R.E. Prakash S. Prakash L. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3838-3843Crossref PubMed Scopus (165) Google Scholar) and pol κ by others (47Ohashi E. Ogi T. Kusumoto R. Iwai S. Masutani C. Hanaoka F. Ohmori H. Genes Dev. 2000; 14: 1589-1594PubMed Google Scholar, 48Zhang Y. Yuan F. Wu X. Wang M. Rechkoblit O. Taylor J.S. Geacintov N.E. Wang Z. Nucleic Acids Res. 2000; 28: 4138-4146Crossref PubMed Google Scholar, 49Gerlach V.L. Feaver W.J. Fischhaber P.L. Friedberg E.C. J. Biol. Chem. 2001; 276: 92-98Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). The name pol θ was previously assigned to a putative polymerase involved in cross-link repair (50Sharief F.S. Vojta P.J. Ropp P.A. Copeland W.C. Genomics. 1999; 59: 90-96Crossref PubMed Scopus (98) Google Scholar). The name pol κ was given also to a yeast polymerase involved in sister chromatid cohesion (51Wang Z. Castano I.B. De Las Penas A. Adams C. Christman M.F. Science. 2000; 289: 774-779Crossref PubMed Scopus (163) Google Scholar). This nomenclature problem will hopefully be resolved in the near future (P. Burgers, manuscript in preparation). (46Johnson R.E. Prakash S. Prakash L. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3838-3843Crossref PubMed Scopus (165) Google Scholar, 47Ohashi E. Ogi T. Kusumoto R. Iwai S. Masutani C. Hanaoka F. Ohmori H. Genes Dev. 2000; 14: 1589-1594PubMed Google Scholar, 48Zhang Y. Yuan F. Wu X. Wang M. Rechkoblit O. Taylor J.S. Geacintov N.E. Wang Z. Nucleic Acids Res. 2000; 28: 4138-4146Crossref PubMed Google Scholar, 52Ohashi E. Bebenek K. Matsuda T. Feaver W.J. Gerlach V.L. Friedberg E.C. Ohmori H. Kunkel T.A. J. Biol. Chem. 2000; 275: 39678-39684Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar). The biological functions of these polymerases are unknown yet. pol ι is distinguished by its remarkable violation of the base pairing rules common to all known DNA polymerases; it prefers to insert dGMP opposite a template T (31Johnson R.E. Washington M.T. Haracska L. Prakash S. Prakash L. Nature. 2000; 406: 1015-1019Crossref PubMed Scopus (585) Google Scholar, 44Tissier A. McDonald J.P. Frank E.G. Woodgate R. Genes Dev. 2000; 14: 1642-1650PubMed Google Scholar, 45Zhang Y. Yuan F. Wu X. Wang Z. Mol. Cell. Biol. 2000; 20: 7099-7108Crossref PubMed Scopus (189) Google Scholar). Surprisingly it was found that pol ι has an associated deoxyribose-phosphate lyase activity, similar to that of pol β (53Bebenek K. Tissier A. Frank E.G. McDonald J.P. Prasad R. Wilson S.H. Woodgate R. Kunkel T.A. Science. 2001; 291: 2156-2158Crossref PubMed Scopus (172) Google Scholar). This the possibility that pol ι is a polymerase to a mutagenic T in a in a the was formed by of (53Bebenek K. Tissier A. Frank E.G. McDonald J.P. Prasad R. Wilson S.H. Woodgate R. Kunkel T.A. Science. 2001; 291: 2156-2158Crossref PubMed Scopus (172) Google Scholar). pol κ has the to bypass some lesions in (47Ohashi E. Ogi T. Kusumoto R. Iwai S. Masutani C. Hanaoka F. Ohmori H. Genes Dev. 2000; 14: 1589-1594PubMed Google Scholar, 48Zhang Y. Yuan F. Wu X. Wang M. Rechkoblit O. Taylor J.S. Geacintov N.E. Wang Z. Nucleic Acids Res. 2000; 28: 4138-4146Crossref PubMed Google Scholar), and the other DNA polymerases of its family, it is mutagenic on undamaged DNA (46Johnson R.E. Prakash S. Prakash L. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 3838-3843Crossref PubMed Scopus (165) Google Scholar, 52Ohashi E. Bebenek K. Matsuda T. Feaver W.J. Gerlach V.L. Friedberg E.C. Ohmori H. Kunkel T.A. J. Biol. Chem. 2000; 275: 39678-39684Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, Y. Yuan F. Xin H. Wu X. D. Wang Z. Nucleic Acids Res. 2000; 28: PubMed Google Scholar). However, its biological function is additional new DNA polymerases were in humans, pol and pol These polymerases belong to the family, rather than the pol is similar to It has a high frequency in vitro, and based on its at in of the it was suggested to be involved in the of mutation in the genes O. M. M.A. A. L. EMBO J. 2000; 19: PubMed Google Scholar, S. E. A. A. B. S. F. L. N. Nucleic Acids Res. 2000; 28: PubMed Google Scholar). pol λ is a pol DNA which to be an It be in error-free repair in S. E. A. A. B. S. F. L. N. Nucleic Acids Res. 2000; 28: PubMed Google Scholar, M. O. M.L. M. T. J. A. L. J. Mol. Biol. 2000; PubMed Scopus Google Scholar). E. coli TLR was with by the H. and M. C. Woodgate R. O'Donnell M. Goodman M. H. Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar), and in the of Livneh N.B. G. Livneh Z. Mol. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) and Goodman M. I. R. J. Frank E.G. Woodgate R. O'Donnell M. Goodman M.F. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: PubMed Scopus Google Scholar). it was found that the translesion replication in the of pol and that UmuC is a DNA termed pol V (15Tang M. Shen X. Frank E.G. O'Donnell M. Woodgate R. Goodman M.F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 8919-8924Crossref PubMed Scopus (488) Google Scholar, 16Reuven N.B. Arad G. Maor-Shoshani A. Livneh Z. J. Biol. 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These multiple repair functions of RecA the of the bacterial The in TLR is the which the of a RecA N.B. Arad G. A. Livneh Z. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). This which in the the region and to the dsDNA region to the including the near the lesion N.B. Arad G. A. Livneh Z. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). In the of pol V to the by the RecA which as a N.B. Arad G. A. Livneh Z. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, E.G. J. Woodgate R. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar). of pol V the is by at least three known and UmuD′ with the RecA E.G. J. Woodgate R. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar); UmuD′ with UmuC R. M. C. H. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus (189) Google Scholar, I. Woodgate R. K. Goodman M.F. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar); and UmuC with the No was UmuC and of TLR by pol V requires the of RecA from the DNA near the to of pol V to the DNA This is based on the of of TLR caused by a that