DNA Polymerase λ Mediates a Back-up Base Excision Repair Activity in Extracts of Mouse Embryonic Fibroblasts

Mammalian DNA polymerase (pol) λ is a member of the X-family of DNA polymerases and has striking enzymatic and structural similarities to mammalian DNA pol β. Because pol β provides two important enzymatic activities for base excision repair (BER), we examined whether pol λ might also contribute to BER. We used extracts from mouse embryonic fibroblasts representing wild-type and null genotypes for pol β and pol λ. In combination with neutralizing antibodies against pol β and pol λ, our results show a BER deficiency in the pol λ -/- cell extract compared with extract from isogenic wild-type cells. In addition, the pol λ antibody strongly reduced in vitro BER in the pol β -/- cell extract. These data indicate that pol λ is able to contribute to BER in mouse fibroblast cell extract. Mammalian DNA polymerase (pol) λ is a member of the X-family of DNA polymerases and has striking enzymatic and structural similarities to mammalian DNA pol β. Because pol β provides two important enzymatic activities for base excision repair (BER), we examined whether pol λ might also contribute to BER. We used extracts from mouse embryonic fibroblasts representing wild-type and null genotypes for pol β and pol λ. In combination with neutralizing antibodies against pol β and pol λ, our results show a BER deficiency in the pol λ -/- cell extract compared with extract from isogenic wild-type cells. In addition, the pol λ antibody strongly reduced in vitro BER in the pol β -/- cell extract. These data indicate that pol λ is able to contribute to BER in mouse fibroblast cell extract. Cells are constantly exposed to environmental stress agents, endogenous reactive oxygen species and alkylating molecules, and other reactive metabolites that are capable of modifying DNA. Cells have several mechanisms by which they protect themselves from the detrimental effects of genotoxic compounds. Base excision repair (BER) 1The abbreviations used are: BER, base excision repair; APE, apurinic/apyrimidinic endonuclease; dRP, 5′-deoxyribose phosphate; pol, polymerase; UDG, uracil-DNA glycosylase; Me2SO, dimethyl sulfoxide; MEF, mouse embryonic fibroblast; MOPS, 3-(N-morpholino)propanesulfonic acid. is the predominant DNA repair system in mammalian cells for eliminating discrete DNA base lesions (1Krokan H.E. Nilsen H. Skorpen F. Otterlei M. Slupphaug G. FEBS Lett. 2000; 476: 73-77Crossref PubMed Scopus (311) Google Scholar). Single-nucleotide BER, one subpathway of BER, results in replacement of only the modified nucleotide and is initiated by a lesion-specific DNA glycosylase. Monofunctional DNA glycosylases hydrolyze the glycosidic bond between the sugar and base of the damaged nucleotide, whereas bifunctional DNA glycosylases excise the damaged base and cleave the phosphodiester backbone 3′ to the resulting abasic site. In the former case, the resulting apurinic/apyrimidinic site is cleaved by apurinic/apyrimidinic endonuclease (APE), producing a single-strand DNA break. DNA polymerase gap-filling DNA synthesis and 5′-deoxyribose phosphate (dRP) removal generates the substrate for the final BER step, DNA ligation. In higher organisms, DNA polymerase (pol) β is thought to be the primary DNA polymerase recruited for BER of lesions generated by monofunctional alkylating agents and reactive oxygen species (2Sobol R.W. Horton J.K. Kuhn R. Gu H. Singhal R.K. Prasad R. Rajewsky K. Wilson S.H. Nature. 1996; 379: 183-186Crossref PubMed Scopus (790) Google Scholar, 3Horton J.K. Joyce-Gray D.F. Pachkowski B.F. Swenberg J.A. Wilson S.H. DNA Repair. 2003; 2: 27-48Crossref PubMed Scopus (83) Google Scholar, 4Fortini P. Parlanti E. Sidorkina O.M. Laval J. Dogliotti E. J. Biol. Chem. 1999; 274: 15230-15236Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 5Nealon K. Nicholl I.D. Kenny M.K. Nucleic Acids Res. 1996; 24: 3763-3770Crossref PubMed Scopus (59) Google Scholar, 6Singhal R.K. Prasad R. Wilson S.H. J. Biol. Chem. 1995; 270: 949-957Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, 7Dianov G. Price A. Lindahl T. Mol. Cell. Biol. 1992; 12: 1605-1612Crossref PubMed Scopus (265) Google Scholar). Pol β contributes both gap-filling DNA synthesis and 5′-dRP lyase activities to the overall BER reaction. However, the contribution of other DNA polymerases to BER has been well documented both in vitro (4Fortini P. Parlanti E. Sidorkina O.M. Laval J. Dogliotti E. J. Biol. Chem. 1999; 274: 15230-15236Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 8Dianov G. Bischoff C. Piotrowski J. Bohr V.A. J. Biol. Chem. 1998; 273: 33811-33816Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar) and in vivo (9Miller M.R. Chinault D.N. J. Biol. Chem. 1982; 257: 10204-10209Abstract Full Text PDF PubMed Google Scholar). Another candidate BER DNA polymerase, DNA pol λ, has been identified that shares many biochemical features with pol β and Saccharomyces cerevisiae DNA pol IV (10Garcia-Diaz M. Dominguez O. Lopez-Fernandez L.A. de Lera L.T. Saniger M.L. Ruiz J.F. Parraga M. Garcia-Ortiz M.J. Kirchhoff T. del Mazo J. Bernad A. Blanco L. J. Mol. Biol. 2000; 301: 851-867Crossref PubMed Scopus (249) Google Scholar, 11Nagasawa K. Kitamura K. Yasui A. Nimura Y. Ikeda K. Hirai M. Matsukage A. Nakanishi M. J. Biol. Chem. 2000; 275: 31233-31238Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 12Prasad R. Widen S.G. Singhal R.K. Watkins J. Prakash L. Wilson S.H. Nucleic Acids Res. 1993; 21: 5301-5307Crossref PubMed Scopus (73) Google Scholar, 13Shimizu K. Santocanale C. Ropp P.A. Longhese M.P. Plevani P. Lucchini G. Sugino A. J. Biol. Chem. 1993; 268: 27148-27153Abstract Full Text PDF PubMed Google Scholar). Like pol β, pol λ is a member of the X-family of DNA polymerases and shares substantial amino acid sequence identity with pol β (10Garcia-Diaz M. Dominguez O. Lopez-Fernandez L.A. de Lera L.T. Saniger M.L. Ruiz J.F. Parraga M. Garcia-Ortiz M.J. Kirchhoff T. del Mazo J. Bernad A. Blanco L. J. Mol. Biol. 2000; 301: 851-867Crossref PubMed Scopus (249) Google Scholar, 11Nagasawa K. Kitamura K. Yasui A. Nimura Y. Ikeda K. Hirai M. Matsukage A. Nakanishi M. J. Biol. Chem. 2000; 275: 31233-31238Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 14Aoufouchi S. Flatter E. Dahan A. Faili A. Bertocci B. Storck S. Delbos F. Cocea L. Gupta N. Weill J.C. Reynaud C.A. Nucleic Acids Res. 2000; 28: 3684-3693Crossref PubMed Google Scholar). Sequence and structural analyses reveal that pol λ contains both of the pol β functional domains, the polymerase domain with functionally distinct subdomains and the dRP lyase domain. Many amino acid residues involved in DNA binding, nucleotide binding, nucleotide selection, and catalysis that have been identified for pol β are conserved in pol λ (10Garcia-Diaz M. Dominguez O. Lopez-Fernandez L.A. de Lera L.T. Saniger M.L. Ruiz J.F. Parraga M. Garcia-Ortiz M.J. Kirchhoff T. del Mazo J. Bernad A. Blanco L. J. Mol. Biol. 2000; 301: 851-867Crossref PubMed Scopus (249) Google Scholar, 15Garcia-Diaz M. Bebenek K. Krahn J.M. Blanco L. Kunkel T.A. Pedersen L.C. Mol. Cell. 2004; 13: 561-572Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 16Garcia-Diaz M. Bebenek K. Sabariegos R. Dominguez O. Rodriguez J. Kirchhoff T. Garcia-Palomero E. Picher A.J. Juarez R. Ruiz J.F. Kunkel T.A. Blanco L. J. Biol. Chem. 2002; 277: 13184-13191Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). In fact, pol λ shares two key BER characteristics with pol β, gap-filling DNA synthesis activity and dRP lyase activity (16Garcia-Diaz M. Bebenek K. Sabariegos R. Dominguez O. Rodriguez J. Kirchhoff T. Garcia-Palomero E. Picher A.J. Juarez R. Ruiz J.F. Kunkel T.A. Blanco L. J. Biol. Chem. 2002; 277: 13184-13191Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 17Garcia-Diaz M. Bebenek K. Kunkel T.A. Blanco L. J. Biol. Chem. 2001; 276: 34659-34663Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). These activities allow pol λ to substitute for pol β in a single-nucleotide BER system reconstituted with purified human proteins (17Garcia-Diaz M. Bebenek K. Kunkel T.A. Blanco L. J. Biol. Chem. 2001; 276: 34659-34663Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). As with pol β, pol λ is a distributive enzyme on open (i.e. not gapped) template primer substrates; however, it is processive on substrates containing a small gap with a 5′-phosphate group (16Garcia-Diaz M. Bebenek K. Sabariegos R. Dominguez O. Rodriguez J. Kirchhoff T. Garcia-Palomero E. Picher A.J. Juarez R. Ruiz J.F. Kunkel T.A. Blanco L. J. Biol. Chem. 2002; 277: 13184-13191Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Pol λ contains a relatively long N-terminal region that has no counterpart in pol β. This region is similar to the N-terminal region of S. cerevisiae DNA pol IV and contains a BRCA1 C-terminal domain and serine-threonine-proline-rich domain (10Garcia-Diaz M. Dominguez O. Lopez-Fernandez L.A. de Lera L.T. Saniger M.L. Ruiz J.F. Parraga M. Garcia-Ortiz M.J. Kirchhoff T. del Mazo J. Bernad A. Blanco L. J. Mol. Biol. 2000; 301: 851-867Crossref PubMed Scopus (249) Google Scholar, 14Aoufouchi S. Flatter E. Dahan A. Faili A. Bertocci B. Storck S. Delbos F. Cocea L. Gupta N. Weill J.C. Reynaud C.A. Nucleic Acids Res. 2000; 28: 3684-3693Crossref PubMed Google Scholar). Although the functions of this N-terminal region are not yet clear, it could promote enzyme localization through protein-protein interactions and could also be a target for post-translational modifications (10Garcia-Diaz M. Dominguez O. Lopez-Fernandez L.A. de Lera L.T. Saniger M.L. Ruiz J.F. Parraga M. Garcia-Ortiz M.J. Kirchhoff T. del Mazo J. Bernad A. Blanco L. J. Mol. Biol. 2000; 301: 851-867Crossref PubMed Scopus (249) Google Scholar). The idea that the BRCA1 C-terminal domain may facilitate protein-protein interactions is supported by a previous study showing that the BRCA1 C-terminal domain is required for efficient gap-filling activity by pol λ and S. cerevisiae DNA pol IV during non-homologous end-joining in vitro (18Lee J.W. Blanco L. Zhou T. Garcia-Diaz M. Bebenek K. Kunkel T.A. Wang Z. Povirk L.F. J. Biol. Chem. 2004; 279: 805-811Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, 19Tseng H.M. Tomkinson A.E. J. Biol. Chem. 2002; 277: 45630-45637Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, 20Wilson T.E. Lieber M.R. J. Biol. Chem. 1999; 274: 23599-23609Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). Other biochemical properties of the enzyme support a role for pol λ in non-homologous end-joining (21Ramadan K. Shevelev I.V. Maga G. Hubscher U. J. Biol. Chem. 2002; 277: 18454-18458Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 22Ramadan K. Maga G. Shevelev I.V. Villani G. Blanco L. Hubscher U. J. Mol. Biol. 2003; 328: 63-72Crossref PubMed Scopus (70) Google Scholar). Despite the extensive analyses of pol λ so far, its possible cellular functions in BER are not yet established. Although in vitro studies have clearly shown that the purified pol λ enzyme is capable of supporting BER reactions, it remains unclear whether the enzyme is expressed in sufficient amounts to support BER in the cell or whether the enzyme is modified in a manner that would prevent its involvement in the BER process. In an effort to further clarify the role of this enzyme in BER, we performed a series of in vitro BER assays with extracts from genetically modified mouse cells lacking functional pol λ alleles. Materials—Synthetic oligodeoxyribonucleotides were from Oligos Etc, Inc. [α-32P]dCTP (3000 Ci/mmol) from Ci/mmol) from from T.A. Wilson S.H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google pol β J. D.N. B. Widen S.G. Wilson S.H. PubMed Scopus Google Scholar, A. Widen S.G. P. Wilson S.H. J. Biol. Chem. Full Text PDF PubMed Google human uracil-DNA G. B. S. T. H.E. 1995; PubMed Scopus Google Scholar) and DNA J. J.M. Tomkinson A.E. J. Biol. Chem. Full Text PDF PubMed Google Scholar) were purified and antibodies against pol β were R.K. Prasad R. Wilson S.H. J. Biol. Chem. 1995; 270: 949-957Abstract Full Text Full Text PDF PubMed Scopus (294) Google whereas antibodies for human pol λ were for this study by of E. Scholar). The mouse and antibodies were and and both were from Pol antibodies were a from and Blanco de and were from cells and and DNA polymerase were from from and from β cells used were a of the wild-type mouse embryonic fibroblast cell Pol β -/- cells were a of the isogenic pol (2Sobol R.W. Horton J.K. Kuhn R. Gu H. Singhal R.K. Prasad R. Rajewsky K. Wilson S.H. Nature. 1996; 379: 183-186Crossref PubMed Scopus (790) Google Scholar). Pol λ and -/- primary were a from Bertocci and Reynaud de de and were generated from a pol λ B. A. Flatter E. Dahan A. J.C. C. Weill J.C. Reynaud C.A. J. 2002; PubMed Scopus Google Scholar). Pol λ and -/- primary were in a in modified containing and of Pol λ and Pol λ -/- cell of primary cells were with the which Cells were with containing and DNA for The with and the cells were for an Cells were a of characteristics of cells were (i.e. in cell of cells were by a of to cell well in a were from cell were R.W. Prasad R. A. A. Horton J.K. Wilson S.H. Nature. 2000; PubMed Scopus Google Scholar). In cells were with by by and in and of and The for and the resulting extract by for in and in vitro BER The of the extract by a performed A. E. Prasad R. Horton J.K. Wilson S.H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). extract by and to The were with in containing and for with primary antibodies against pol β, pol λ, or the were with activity by an system In BER with of cell extract were a single-nucleotide BER in a final of J.K. A. R.W. Wilson S.H. DNA Repair. 2002; PubMed Scopus (73) Google Scholar). containing with cell extract for in a BER containing and The repair initiated by the final to and [α-32P]dCTP In addition, were with The for and BER were J.K. A. R.W. Wilson S.H. DNA Repair. 2002; PubMed Scopus (73) Google Scholar). In vitro BER were performed in a similar of cell extract were a single-nucleotide BER in a final of containing with cell extract in the BER with and [α-32P]dCTP The and of the were for the BER were J.K. A. R.W. Wilson S.H. DNA Repair. 2002; PubMed Scopus (73) Google Scholar). reconstituted BER also performed similar the human UDG, APE, DNA and pol β, or pol λ. BER were Prasad R. Tomkinson A.E. Wilson S.H. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). on in a that DNA and of The and were The by of and the were Prasad R. Tomkinson A.E. Wilson S.H. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). and were used of for Pol human pol λ from and by primer and primer that an site with an and a site with a The and of the pol λ sequence are and The with the and and a The resulting λ, the open for human pol λ with a the λ the of DNA from and the sequence of pol λ by DNA and of Pol λ from with λ in of that and to target Cells were to an of the cells were by and in containing to an of and to for to a final of and for Cells were by and in and and containing The cell and by for The cell with to the to and through a that with containing The and and were to the final to and This to a of on that with with and The in sequence with of with and containing and to the were with a in containing were and and were to to final of and of a system and containing pol λ were and with containing to the to The to a with and and with an to in C. were and containing pol λ were The with to the to and to a the with the proteins were a in C. containing pol λ were and to a the step, the and in and by In BER with DNA cell extracts support a of biochemical they a the a cell and a for the biochemical activity of a and the of are biochemical that have the to be in a cell extract. in an effort to further pol λ in the of a series of cell BER were performed with the cell used in this study were by to of pol β and λ. As shown in pol λ in the pol λ -/- cell and the of pol λ in the pol β and -/- cell In addition, the of pol β in the pol λ and -/- cell containing with extracts from cell of the substrate by the extract used to repair the and As from previous (2Sobol R.W. Horton J.K. Kuhn R. Gu H. Singhal R.K. Prasad R. Rajewsky K. Wilson S.H. Nature. 1996; 379: 183-186Crossref PubMed Scopus (790) Google the pol β -/- cell extract a BER deficiency in this compared with extract from the wild-type cell However, pol β -/- cell extract repair and this clearly with the of a pol BER from pol λ -/- on the other no repair compared with the wild-type cell for of Pol BER in pol β is an enzyme in the BER it is to the contribution of BER polymerases in its In an effort to this an antibody against pol β used to its activity a possible role of pol λ in BER. This pol antibody for its and the antibody for its to pol β activity in a wild-type extract. or no on BER activity the pol β antibody DNA repair synthesis to a similar to the results with pol β -/- cell extract and that were for and the from repair activity The of antibody used in the of pol β activity in a wild-type cell extract Because both β and λ to the X-family and many structural and biochemical we to that the antibody to pol β and not pol λ in vitro BER system with purified UDG, APE, pol β, or pol λ and DNA used in this Prasad R. Tomkinson A.E. Wilson S.H. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). In with pol β, the antibody against pol β strongly reduced both and BER however, in with pol λ, this antibody on DNA repair synthesis These indicate that the neutralizing antibody against pol β not the activity of pol λ. of Pol BER in the of Pol β the pol β we the role of pol λ in BER. Pol λ -/- and isogenic wild-type cell extracts were and used in an in vitro BER for extracts were with or the antibody against pol β the wild-type cell extract with pol β the of BER a substantial of BER that a similar performed with pol λ -/- cell the of BER DNA and BER that with the pol λ cell extract with both pol β and pol λ activities were by antibody and BER activity in the of of and is that in the of pol β and λ, extracts were able to BER a reduced for of Pol in a BER a of pol λ with the of the pol for pol BER were during of this We examined the effects of a series of DNA polymerase in our in vitro BER to reveal an with pol λ not we that the pol As in an in BER activity in the pol β -/- cell extract in the that amounts of cell extracts with Me2SO, DNA repair a of extract a This with a previous study a of mammalian cell DNA repair synthesis by G. Price A. Lindahl T. Mol. Cell. Biol. 1992; 12: 1605-1612Crossref PubMed Scopus (265) Google Scholar). In addition, have used to DNA polymerase through a Nucleic Acids Res. PubMed Scopus Google Scholar, H. J.M. H. F. R. U. S. A. 2004; PubMed Scopus Google Scholar). further the of on pol BER by the cell we BER a of DNA in the The of repair on the of DNA substrate in the and of Me2SO, however, the activity (i.e. of the in the of The results that BER activity in the pol β -/- pol by The idea that pol repair is supported by the that not have a on the of BER activity in pol λ -/- cell extracts In addition, a reconstituted BER system with purified the containing purified pol λ, whereas the system with pol β of BER with to pol neutralizing antibodies against both pol λ and pol β were used to a role of pol λ in in vitro BER. a pol antibody a reconstituted BER system to whether the antibody pol BER activity the used in our As shown in no on the BER activity of pol λ and However, the pol antibody reduced BER activity to for this antibody used to the role of pol λ in BER. extract from the pol β -/- cell with or antibody against pol λ As in no on BER whereas the neutralizing antibody against pol λ reduced repair to a for In the we used extracts from pol λ and pol λ -/- cells in the of pol β antibody to the role of pol λ. the pol λ cell extract with pol β antibody a substantial of BER the pol λ -/- cell the of BER that with the pol λ cell extract and We from results that pol λ in BER. In this we that the of pol λ in mammalian cell BER an open study the of the purified human pol λ to in an in vitro BER system with several other purified BER (17Garcia-Diaz M. Bebenek K. Kunkel T.A. Blanco L. J. Biol. Chem. 2001; 276: 34659-34663Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). This however, not whether pol λ could a BER role in cell mouse The to a BER on whether or not the enzyme is expressed in cells. This is an important in a role for pol λ in BER of its DNA polymerase activity that of pol data not in in which pol λ is expressed a the enzyme may not be of post-translational modifications or for pol λ to be in the cell extracts the enzyme be expressed a substantial and it be and for to the BER of were by the previous with purified pol λ. biochemical and are to the of pol λ. In of the results our of pol λ. In the the of enzyme in against DNA base has been assays with cells a null in the In a role of pol β in against agents exposed in this (2Sobol R.W. Horton J.K. Kuhn R. Gu H. Singhal R.K. Prasad R. Rajewsky K. Wilson S.H. Nature. 1996; 379: 183-186Crossref PubMed Scopus (790) Google Scholar, R.W. Prasad R. A. A. Horton J.K. Wilson S.H. Nature. 2000; PubMed Scopus Google Scholar). Despite the pol cell to agents, a of to the idea that pol BER may in cells. that polymerases also the polymerase role in BER Y. K. D.F. Mol. Cell. Biol. PubMed Scopus Google Scholar, S. R.W. Wilson S.H. Y. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, M. B. Parlanti E. P. Wilson S.H. Hubscher U. Dogliotti E. 1998; PubMed Scopus Google Scholar, P. B. Parlanti E. R.W. Wilson S.H. Dogliotti E. 1998; PubMed Scopus Google a system for the pol β In addition, other mammalian DNA polymerases could a role a in BER in the pol β pol λ would to be an Because pol λ is to pol β and two key biochemical activities that for a possible role in BER lyase and gap-filling (16Garcia-Diaz M. Bebenek K. Sabariegos R. Dominguez O. Rodriguez J. Kirchhoff T. Garcia-Palomero E. Picher A.J. Juarez R. Ruiz J.F. Kunkel T.A. Blanco L. J. Biol. Chem. 2002; 277: 13184-13191Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar, 17Garcia-Diaz M. Bebenek K. Kunkel T.A. Blanco L. J. Biol. Chem. 2001; 276: 34659-34663Abstract Full Text Full Text PDF PubMed Scopus (219) Google we whether pol λ is capable of a BER activity in This by the in vitro BER of extracts from pol in vitro BER assays were performed an BER activity As has been well pol β -/- cell extract BER activity (4Fortini P. Parlanti E. Sidorkina O.M. Laval J. Dogliotti E. J. Biol. Chem. 1999; 274: 15230-15236Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 8Dianov G. Bischoff C. Piotrowski J. Bohr V.A. J. Biol. Chem. 1998; 273: 33811-33816Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, P. B. Parlanti E. R.W. Wilson S.H. Dogliotti E. 1998; PubMed Scopus Google Scholar, P. B. F. Dogliotti E. Nucleic Acids Res. 2000; 28: PubMed Google Scholar). of containing in the pol λ or pol β and neutralizing antibodies against proteins to we that pol λ -/- extract reduced BER compared with the pol λ extract and that a neutralizing antibody against pol λ pol repair to We that pol λ capable of to a of this in vitro BER activity in this on the of pol λ to in BER, it be to cellular to DNA agents to whether pol λ a role in the against DNA This would be by the of a pol β pol λ -/- cell cell by small or of mouse may the role by enzyme in against of DNA We Bertocci and Reynaud de de for the pol λ and -/- primary mouse embryonic fibroblast and A. Kunkel of for and Blanco de for the neutralizing antibody against pol and and for of this

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