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Overexpression of DNA polymerase ß: a genomic instability enhancer process

IPBS - CNRS UPR 9062, groupe Instabilité Génétique et Cancer, 31077 Toulouse cedex, France

¹Correspondence: Jean-Sébastien Hoffmann (jseb@ipbs.fr) and Christophe Cazaux, IPBS - CNRS UPR 9062, groupe Instabilité Génétique et Cancer, 205 route de Narbonne, 31077 Toulouse cedex, France.

	ABSTRACT

TOP ABSTRACT INTRODUCTION POL ss AND DNA... REPLICATIVE BYPASS OF DNA... POL ss AND REPAIR... POL ss ACTIVITY IN... HOW TO TEST THESE... REFERENCES

 
DNA polymerase ß (Pol ß) is the most inaccurate of the six DNA polymerases found in mammalian cells. In a normal situation, it is expressed at a constant low level and its role is believed to be restricted to repair synthesis in the base excision repair pathway participating to the genome stability. However, excess of Pol ß, found in some human tumors, could confer an increase in spontaneous mutagenesis and result in a highly mutagenic tolerance phenotype toward bifunctional DNA cross-linking anticancer drugs. Here, we present a hypothesis on the mechanisms used by Pol ß to be a genetic instability enhancer through its overexpression. We hypothesize that an excess of Pol ß perturbs the well-defined specific functions of DNA polymerases developed by the cell and propose Pol ß-mediated gap fillings during DNA transactions like repair, replication, or recombination pathways as key processes to introduce illegitimate deoxyribonucleotides or mutagenic base analogs like those produced by intracellular oxidative processes. These mechanisms may predominate during cellular nonproliferative phases in the absence of DNA replication.—Canitrot, Y., Fréchet, M., Servant, L., Cazaux, C., Hoffmann, J.-S. Overexpression of DNA polymerase ß: a genomic instability enhancer process.

Key Words: DNA replication • Pol ß • mismatch repair • nucleotide excision repair

	INTRODUCTION

TOP ABSTRACT INTRODUCTION POL ss AND DNA... REPLICATIVE BYPASS OF DNA... POL ss AND REPAIR... POL ss ACTIVITY IN... HOW TO TEST THESE... REFERENCES

 
GENETIC INSTABILITY WAS one of the main characteristics postulated to underlie neoplasia. It occurs in two different pathways, one resulting in an increased mutation rate at the nucleotide level and the other corresponding to chromosomal instability leading to an abnormal chromosome number. Perturbation in DNA transactions like repair, replication, or recombination generate increased genetic instability at the nucleotide level (1) . During these transactions, the substrates of DNA polymerases vary from single nucleotide gaps to kilobase-sized gaps and from simple gapped structures to complex replication forks, in which two strands need to be replicated coordinately. Consequently, the cells seem to have evolved a well-defined set of DNA polymerases, each one uniquely adapted for a specific pathway (2) . DNA polymerase is required for the initiation of DNA replication and the priming of Okazaki fragments during elongation (3) . DNA polymerase , which functions as a dimer in both leading and lagging strand synthesis, is required for mismatch repair (MMR)² (4) and nucleotide excision repair (NER) (5) , as well as long-patch base excision repair (BER) (6) . DNA polymerase is thought to be restricted to the Okazaki fragment maturation function. According to the current consensus, DNA polymerase ß (Pol ß) is the BER polymerase (7) that is expressed at a constant low level throughout the cell cycle (8) and is inducible by some genotoxic treatments (9) . Features that distinguish pol ß from other cellular polymerases are the lack of associated proofreading activity, its low fidelity in replicating DNA in vitro (10) , and its poor ability to discriminate nucleotides at the level of binding (11, 12) . In accordance with its low accuracy, Pol ß exhibits the lowest discrimination against mutagenic analogs of dGTP modified by endogenous processes (13) and has the potential to efficiently catalyze error-prone translesion synthesis in vitro across intrastrand cross-links (14) . Evidence suggests, however, that the accuracy of Pol ß may be greater when incorporating a single nucleotide (15) .

By using an eukaryotic expression system, we recently demonstrated that overexpression of Pol ß in cells resulted in an increased rate of spontaneous mutagenesis as well as a highly mutagenic tolerance phenotype to bifunctional cross-linking agents used in cancer chemotherapy such as cisplatin, melphalan, and mechlorethamine, which suggests that the enzyme may have a role in cancer predisposition and tumor progression (16) . Recent observations from our group showed that a significantly higher expression of Pol ß occurs in some tumor cell lines such as leukemia (17) and ovarian cancer cells (unpublished data). In addition, increases in Pol ß mRNA and protein were observed in several tumor cell lines resistant to cisplatin, including ovarian, colon, and leukemia cells (18) . From the X-ray crystal structure of Pol ß (19) , it appears that the enzyme forms a U-like cleft that could accommodate DNA. By analogy to a hand, the three sides of the cleft are referred to as fingers, palm, and thumb. Recent structural and kinetic analysis of active-site mutants indicates that Pol ß selects the correct incoming dNTP by stabilizing the template base through conformational changes, forming an active site that examines the geometric properties of the new base pair (20) . Correct alignment of the template base is necessary for the polymerase to examine accurately the steric complementarity inherent in the Watson-Crick base pair (20) . The nucleotide insertion fidelity of Pol ß has been shown to be much higher (10–100 times) on 5'-phosphorylated single-nucleotide gapped DNA than with other long single-stranded DNA substrates (15) , suggesting that inaccurate DNA replication on larger gapped DNA by overexpressed Pol ß could be at the origin of the genomic instability. The dynamic role that the single-stranded template strand plays in Pol ß fidelity has been appreciated. The enzyme must interact with the template strand so as to position the coding template base in the correct alignment and register. Failure to do so can result in base substitution or deletion errors. The tendency of Pol ß to make -1 frameshifts suggests that with long single-stranded DNA regions, the template strand has a propensity to misalign (20) .

We propose here that overexpression of Pol ß may destabilize the well-defined set of DNA polymerases developed by the cells, with each one specifically involved in a pathway. Overexpression may hijack Pol ß to repair pathways other than BER short patch, some of which may involve longer single-stranded DNA (these hypotheses are illustrated in Fig. 1 ). Involvement of Pol ß in such pathways could promote error-prone DNA synthesis, a source for genetic instability. We present hypotheses regarding the different processes Pol ß can interfere with in order to affect genomic stability.

View larger version (18K): [in this window] [in a new window]   Figure 1. The potential error-prone DNA synthesis pathways for overexpressed DNA polymerase ß. Bold lines depict the inaccurate DNA polymerization catalyzed by Pol ß. In all of these processes [base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), lagging strand DNA replication, and translesion synthesis], a step involves an intermediate gapped DNA that has to be filled by a DNA polymerase activity. The DNA lesion in the <<translesion replication>> pathway is presented as a black circle.

	POL ß AND DNA REPLICATION

TOP ABSTRACT INTRODUCTION POL ss AND DNA... REPLICATIVE BYPASS OF DNA... POL ss AND REPAIR... POL ss ACTIVITY IN... HOW TO TEST THESE... REFERENCES

 
Human cell DNA replication is a well-orchestrated event requiring the coordinated activity of a number of enzymes and proteins. This efficient orchestration is accomplished by a physically and functionally organized multiprotein complex called the DNA synthesome, which contains the DNA polymerases , , and , a DNA primase, the proliferating cell nuclear antigen (PCNA), the topoisomerases I and II, the replication protein A (RPA), the replication factor C (RF-C), a DNA helicase, the poly(ADP) ribose polymerase (PARP), and a DNA ligase (3, 21) . Additional studies are needed to establish the stoichiometry of this complex.

Current approaches to the reconstitution of the mammalian DNA replication fork derive from numerous works describing the replication of SV40 origin-containing plasmids in cell extracts. These studies demonstrated the role of Pol at the origins and Pol during the elongation steps. The nucleus of eukaryotic cells contains the three DNA polymerases, Pol , , and , each of which is required for viability. It is believed that there is a role for all three polymerases in the process of chromosomal replication. In a normal situation, it is assumed that Pol ß is not involved in the process, although its participation in some aspect of gap filling associated with DNA replication has been suggested as an optional pathway (3) . At a replication fork, lagging strand synthesis requires the joining of Okazaki fragments. In eukaryotic cells, the ribonucleotides of the 6–14 bp RNA primers for the Okazaki fragments are removed by the action of a RNase H, followed by flap endonuclease (FEN-1), exonuclease, or endonuclease activity (22) . Subsequent DNA synthesis in order to fill the gap, followed by ligation, closes the process. The DNA polymerase identity involved at this stage is uncertain. It has been proposed that the function of Pol in DNA replication is restricted to this maturation process of the Okazaki fragments (2) . We propose that the presence of such gapped DNA on lagging strand of the replication forks could be a target for an overexpressed Pol ß, which could therefore participate directly in the DNA replication process by competing with the replicative enzymes or by completing their actions. In this respect, it was demonstrated that the expression of Pol ß in Escherichia coli could restore growth in a DNA polymerase I-defective bacterial mutant by increasing the rate of joining of Okazaki fragments, suggesting that Pol ß can also function in DNA replication (23) . Thus, these processes may introduce illegitimate nucleotides, a source of mutagenesis.

	REPLICATIVE BYPASS OF DNA DAMAGE

TOP ABSTRACT INTRODUCTION POL ss AND DNA... REPLICATIVE BYPASS OF DNA... POL ss AND REPAIR... POL ss ACTIVITY IN... HOW TO TEST THESE... REFERENCES

 
Replication forks may often encounter endogenous or exogenous damages in the DNA template before they are repaired. In vitro and in vivo capacity of replicative bypass of these lesions has been documented in several studies. In cases where the coding properties of a damaged base are altered, such translesion synthesis can be mutagenic. This process has been investigated in budding yeast, Saccharomyces cerevisiae, whose gene REV3 encodes the catalytic subunit of DNA polymerase , which is thought to carry out translesion synthesis and to be responsible for virtually all DNA damage-induced mutagenesis (24) . The human homologue of the REV3 gene, which has been recently cloned, appears to carry out a similar function (25) . We demonstrated that calf thymus Pol ß is also able to efficiently bypass a d(GpG) cisplatin adduct in a highly mutagenic process, which most frequently creates single-base deletion mutants (14, 26) . Human Pol ß can also bypass abasic sites in DNA, resulting in both deletions and base substitutions (27) . We recently proposed that overexpression of Pol ß may facilitate translesion replication of bulky DNA adducts formed by bifunctional cross-linking antitumor agents such as cisplatin, melphalan, and mechlorethamine, a process that can accelerate the mutagenesis process and select stronger mutators during chemotherapy of a tumor. It is possible that such a mutagenic process may also occur for endogenous damages, resulting, for example, from oxidative metabolism.

	POL ß AND REPAIR PATHWAYS INVOLVING GAPPED DNA

TOP ABSTRACT INTRODUCTION POL ss AND DNA... REPLICATIVE BYPASS OF DNA... POL ss AND REPAIR... POL ss ACTIVITY IN... HOW TO TEST THESE... REFERENCES

 
Different cellular DNA repair processes have been shown to generate gaps in genomic DNA that need to be filled by DNA polymerases. Among these, three major pathways in mammals for removing different types of DNA alterations are NER, BER, and MMR.

A great variety of lesions in DNA that result in major distortions of the double helical structure are removed by NER. This pathway processes damage by locating the lesion, excising the oligomer carrying the modified nucleotides, and synthesizing a repair patch using the opposite strand as a template (5) . This process in cells and in vitro is sensitive to aphidicolin, which inhibits DNA polymerases , , and . Strong evidence from many sources has led to the conclusion that DNA polymerases or are responsible for NER synthesis. Their role was strengthened by the finding that PCNA is required for NER in mammalian cell extracts (28) . The high accuracy of these DNA polymerases results in an error-free DNA synthesis, explaining why NER is considered as a genomic stability pathway by reestablishing the correct nucleotide sequence. However, in a context of overexpression, Pol ß may interfere by completing the gap-filling synthesis initiated by Pol and , resulting in an error-prone DNA synthesis that can render NER inaccurate.

The BER pathway is the main strategy for the human cells to correct both spontaneous DNA damage and small DNA adducts (29) . Two distinct pathways for completion of BER have been proposed: 1) the short-patch BER involves the replacement of a single nucleotide by the sequential action of a DNA glycosylase, a apurinic/apyrimidic (AP) endonuclease, Pol ß, and a DNA ligase; and 2) the long-patch BER, which involves gap filling of several nucleotides by the same molecular partners except that Pol and/or Pol are required for the DNA synthesis step (6) with the addition of PCNA and Flap endonuclease 1 (FEN-1). The efficiency of Pol ß on 1-nucleotide gap DNA has been shown to be 500- to 10 000-fold higher than on other substrates and the frequency of nucleotide misinsertion by Pol ß was 10- to 100-fold lower on these 1-nt gap DNA (15) . Therefore, the biochemical and fidelity activities of Pol ß are consistent with a role in the accurate short-patch BER. However, its involvement in long-patch BER may enhance the probability for misincorporation. We propose that overexpressed Pol ß in cells can substitute for Pol and or can complete their action in long-patch BER in an inaccurate manner.

DNA MMR proteins act to correct errors that result from nucleotide incorporation mistakes made during DNA replication (30) . In humans, heterodimer complexes composed of homologs of the E. coli proteins MutS and MutL are involved in MMR. The hMutS and hMutSß heterodimers, each containing a subunit of hMSH2 and either a subunit of hMSH6 or hMSH3, bind single-base mismatches and base loops, respectively (31 32 33) . Each hMutS heterodimer is likely to work in concert with a MutL heterodimer composed of hMLH1 and hPMS2, the human homologs of E. coli MutL (30) . After mismatch recognition, the DNA strand with the incorrect base and surrounding sequences up to 1000 bp away are excised and the unmutated strand serves as a template for error-free DNA synthesis. The DNA polymerase involved may need to initiate synthesis of several hundred bases on the 3' or 5' side of a mispair. Such bidirectional mismatch repair by human cell extract is achieved by DNA polymerases and/or , which function with PCNA (34) . Like the NER and long-patch BER situations, implication of the overexpressed Pol ß at this stage may be mutagenic.

	POL ß ACTIVITY IN NONPROLIFERATIVE CELLULAR STATE

TOP ABSTRACT INTRODUCTION POL ss AND DNA... REPLICATIVE BYPASS OF DNA... POL ss AND REPAIR... POL ss ACTIVITY IN... HOW TO TEST THESE... REFERENCES

 
There are many situations where cells are not actively dividing. Because of the low frequency of cell division in most tissues, it may be that the majority of somatic cells are in this resting state most of the time. For cancer cells, obstacles such as nutritional requirement, inadequate blood supply, and impenetrable barriers generated by normal cellular matrices limit their expansion (35) . It has been documented that mutagenic processes can occur in nonproliferative cells (36) and that these processes can be very different from those seen in actively growing cells. Thus, successive periods of nonproliferation could result in an increased number of mutations and facilitate the emergence of mutators. The molecular mechanisms of the mutation accumulation in the absence of DNA replication remain unknown. In contrast to the other DNA polymerases, the level of Pol ß is constant throughout the cell cycle; therefore, its DNA synthesis activity may be predominant in the absence of replication. In bacteria, DNA recombination pathway has been proposed to be associated to mutational events occurring in this process (37) . The implication of the DNA replication-independent DNA synthesis catalyzed by the error-prone activity of Pol ß needs to be investigated in eukaryotic cells. As a component of recombination nodules (38) , Pol ß may interact with the Rad 51 protein responsible for in vitro and in vivo homologous recombination.

	HOW TO TEST THESE HYPOTHESES?

TOP ABSTRACT INTRODUCTION POL ss AND DNA... REPLICATIVE BYPASS OF DNA... POL ss AND REPAIR... POL ss ACTIVITY IN... HOW TO TEST THESE... REFERENCES

 
Numerous biochemical and genetic studies that address polymerase function in DNA replication and DNA repair pathways can easily be used to test all these hypotheses (29, 39) . Replication or repair extracts from mammalian cells overexpressing Pol ß will help to demonstrate the perturbation of these processes by an elevated level of the polymerase. In addition, a transgenic system involving overexpression of Pol ß, which we recently elaborated in our lab (unpublished data), should also provide a novel framework to orient future works on mutagenesis in mammalian cells.

	FOOTNOTES

 
² Abbreviations: BER, base excision repair; MMR, mismatch repair; NER, nucleotide excision repair; PARP, poly(ADP) ribose polymerase; PCNA, proliferating cell nuclear antigen; Pol ß, polymerase ß; RF-C, replication factor C; RPA, replication protein A.

	REFERENCES

TOP ABSTRACT INTRODUCTION POL ss AND DNA... REPLICATIVE BYPASS OF DNA... POL ss AND REPAIR... POL ss ACTIVITY IN... HOW TO TEST THESE... REFERENCES

 

1. Hoffmann, J., Cazaux, C. (1997) DNA synthesis, mismatch repair, and cancer. Int. J. Oncol. 12,377-382
2. Burgers, P. (1998) Eukaryotic DNA polymerases in DNA replication and DNA repair. Chromosoma 107,218-227[Medline]
3. Bambara, R., Huang, L. (1995) Reconstitution of mammalian DNA replication. Prog. Nucleic Acids Res. 51,93-122[Medline]
4. Holmes, J., Clark, S., Modrich, P. (1990) Strand-specific mismatch correction in nuclear extracts of human and Drosophila melanogaster cell lines. Proc. Natl. Acad. Sci. USA. 87,5837-5841[Abstract/Free Full Text]
5. Wood, R. (1997) Nucleotide excision repair in mammalian cells. J. Biol. Chem. 272,23465-23468[Free Full Text]
6. Stucki, M., Pascucci, B., Parlanti, E., Fortini, P., Wilson, S., Hubscher, U., Dogliotti, E. (1998) Mammalian base excision repair by DNA polymerases and . Oncogene 17,835-843[Medline]
7. Sobol, R., Horton, J., Kühn, R., Gu, H., Singhal, R., Prasad, R., Rajewsky, K., Wilson, S. (1996) Requirement of mammalian DNA polymerase-beta in base-excision repair. Nature (London) 379,183-186[Medline]
8. Zmudzka, B., Fornace, A., Collins, J., Wilson, S. (1988) Characterization of DNA polymerase beta mRNA: cell-cycle and growth response in cultured human cells. Nucleic Acids Res 16,9589-9596
9. Fornace, A., Zmudzka, B., Hollander, M., Wilson, S. (1989) Induction of beta-polymerase mRNA by DNA-damaging agents in Chinese hamster ovary cells. Mol. Cell. Biol. 9,851-853[Abstract/Free Full Text]
10. Kunkel, T. (1985) The mutational specificity of DNA polymerase-beta during in vitro DNA synthesis. Production of frameshift, base substitution, and deletion mutations. J. Biol. Chem. 260,5787-5796[Abstract/Free Full Text]
11. Bouayadi, K., Hoffmann, J., Fons, P., Tiraby, M., Reynes, J., Cazaux, C. (1997) Overexpression of DNA polymerase ß sensitizes mammalian cells to 2',3'-dideoxycytidine and 3'-azido-3'-deoxythymidine. Cancer Res 57,110-116[Abstract/Free Full Text]
12. Copeland, W. C., Chen, M. S., Wang, T. S. F. (1992) Human DNA polymerases and ß are able to incorporate anti-HIV deoxynucleotides into DNA. J. Biol. Chem. 267,21459-21464[Abstract/Free Full Text]
13. Kamath-Loeb, A., Hizi, A., Kasai, H., Loeb, L. (1997) Incorporation of the guanosine triphosphate analogs 8-oxo-dGTP and 8-NH2-dGTP by reverse transcriptases and mammalian DNA polymerases. J. Biol. Chem. 272,5892-5898[Abstract/Free Full Text]
14. Hoffmann, J. S., Pillaire, M. J., Maga, G., Podust, V., Hübscher, U., Villani, G. (1995) DNA polymerase ß bypass in vitro d(GpG)-cisplatin adduct placed on codon 13 of H-ras gene. Proc. Natl. Acad. Sci. USA. 92,5356-5360[Abstract/Free Full Text]
15. Chagovetz, A., Sweasy, J. S., Preston, B. (1997) Increased activity and fidelity of DNA polymerase ß on single nucleotide gapped DNA. J. Biol. Chem. 272,27501-27504[Abstract/Free Full Text]
16. Canitrot, Y., Cazaux, C., Fréchet, M., Bouayadi, K., Lesca, C., Salles, B., Hoffmann, J. S. (1998) Overexpression of DNA polymerase beta in cell results in a mutator phenotype and a decreased sensitivity to anticancer drugs. Proc. Natl. Acad. Sci. USA. 95,12586-12590[Abstract/Free Full Text]
17. Canitrot, Y., Lautier, D., Laurent, G., Fréchet, M., Ahmed, A., Turhan, A., Salles, B., Cazaux, C., and Hoffmann, J. S. (1999) Mutator phenotype of BCR-ABL transfected Ba/F3 cell lines and its association with enhanced expression of DNA polymerase ß. Oncogene 18, In press
18. Scanlon, K., Kashani-Sabet, M., Miyachi, H. (1989) Differential gene expression in human cancer cells resistant to cisplatin. Cancer Invest 7,581-587[Medline]
19. Pelletier, H., Sawaya, M., Kumar, A., Wilson, S., Kraut, J. (1994) Structures of ternary complexes of rat DNA polymerase beta, a DNA-template-primer, and ddCTP. Science 264,1891-1903[Abstract/Free Full Text]
20. Beard, W., Wilson, S. (1998) Structural insights into DNA polymerase beta fidelity: hold tight if you want it right. Chem. Biol. 5,R7-R13[Medline]
21. Kornberg, A., and Baker, T. (1992) DNA replication. In DNA Replication, W. H. Freeman, New York
22. Lieber, M. (1997) The FEN-1 family of structure-specific nucleases in eukaryotic DNA replication, recombination and repair. BioEssays 19,233-240[Medline]
23. Sweasy, J., Loeb, L. (1992) Mammalian DNA polymerase beta can substitute for DNA polymerase I during DNA replication in Escherichia coli. J. Biol. Chem. 267,1407-1410[Abstract/Free Full Text]
24. Lawrence, C., Hinkle, D. (1996) DNA polymerase and the control of DNA damage induced mutagenesis in eukaryotes. Cancer Surveys 28,21-31[Medline]
25. Gibbs, P., McGregor, W., Maher, V., Nisson, P., Lawrence, C. (1998) A human homolog of the Saccharomyces cerevisiae REV3 gene, which encodes the catalytic subunit of DNA polymerase zeta. Proc. Natl. Acad. Sci. USA. 95,6876-6880[Abstract/Free Full Text]
26. Hoffmann, J. S., Pillaire, M., Garcia-Estefania, D., Lapalu, S., Villani, G. (1996) In vitro bypass replication of the cisplatin-d(GpG) lesion by calf thymus DNA polymerase ß and human immunodeficiency virus type I reverse transcriptase is highly mutagenic. J. Biol. Chem. 271,15386-15392[Abstract/Free Full Text]
27. Efrati, E., Tocco, G., Eritja, R., Wilson, S., Goodman, M. (1997) Abasic translesion synthesis by DNA polymerase ß violates the `A-rule'. J. Biol. Chem. 272,2559-2569[Abstract/Free Full Text]
28. Shijvi, M., Kenny, M., Wood, R. (1992) Proliferating cell nuclear antigen is required for DNA excision repair. Cell 69,367-374[Medline]
29. Wood, R. (1996) DNA repair in eukaryotes. Annu. Rev. Biochem. 65,135-167[Medline]
30. Kolodner, R. (1996) Biochemistry and genetics of eukaryotic mismatch repair. Genes Dev 10,1433-1442[Free Full Text]
31. Drummond, J., Li, G., Longley, M., Modrich, P. (1995) Isolation of an hMSH2–p160 heterodimer that restores DNA mismatch repair to tumor cells. Science 268,1909-1912[Abstract/Free Full Text]
32. Palombo, F., Gallinari, P., Iaccarino, I., Lettieri, T., Hughes, M., D'arrigo, A., Truong, O., Hsuan, J., Jiricny, J. (1995) GTBP, a 160-kilodalton protein essential for mismatch-binding activity in human cells. Science 268,1912-1914[Abstract/Free Full Text]
33. Palombo, F., Iaccarino, I., Nakajima, E., Ikejima, M., Shimada, T., Jiricny, J. (1996) hMutSbeta, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA. Curr. Biol. 6,1181-1184[Medline]
34. Umar, A., Buermeyer, A., Simon, J., Thomas, D., Clark, A., Liskay, R., Kunkel, T. (1996) Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell 87,65-73[Medline]
35. Loeb, L. (1997) Transient expression of a mutator phenotype in cancer cells. Science 277,1449-1450[Free Full Text]
36. Drake, J. (1991) Spontaneous mutations. Annu. Rev. Genet. 25,125-146[Medline]
37. Torkelson, J., Harris, R., Lombardo, M., Nagendran, J., Thulin, C., Rosenberg, S. (1997) Genome-wide hypermutation in a subpopulation of stationary-phase cells underlies recombination-dependent adaptive mutation. EMBO J 16,3303-3311[Medline]
38. Plug, A., Clairmont, C., Sapi, E., Ashley, T., Sweasy, J. (1997) Evidence for a role of DNA polymerase ß in mammalian meiosis. Proc. Natl. Acad. Sci. USA. 94,1327-1331[Abstract/Free Full Text]
39. Herendeen, D., and Kelly, T. (1996) SV40 replication. In Eukaryotic DNA Replication, pp. 29–65, Oxford University Press, New York

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