Progress toward molecular biology of DNA polymerase β

Wilson, S.H.; Abbotts, John; Widen, Steven G.

doi:10.1016/0167-4781(88)90078-4

Cited by 51 publications

(24 citation statements)

References 29 publications

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“…Pol b is a 39 kDa enzyme involved in the base excision and mismatch forms of DNA repair (Wilson et al, 1988). Inhibition of pol b gene expression by Tax suggested that Tax might suppress DNA repair mediated by this enzyme.…”

Section: Effect Of Tax On Cellular Dna Repairmentioning

confidence: 99%

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

2005

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Section: Effect Of Tax On Cellular Dna Repairmentioning

confidence: 99%

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

2005

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“…Most interestingly, a pol ␤ mutant with an 87-bp deletion, which has been found in primary colorectal, lung, and breast adenocarcinomas (3,5,10), is dominant to the WT enzyme and disrupts its base excision repair (BER) activity if expressed in human cell lines (11,12). It is quite possible that other pol ␤ mutants found in tumor samples have a similar biological impact.BER is an important eukaryotic DNA repair pathway that functions to remove DNA damage, including abasic sites, oxidative lesions, and methylated bases (13,14). It is estimated that BER repairs as many as 10,000 DNA lesions per cell per day (15).…”

mentioning

confidence: 99%

“…BER is an important eukaryotic DNA repair pathway that functions to remove DNA damage, including abasic sites, oxidative lesions, and methylated bases (13,14). It is estimated that BER repairs as many as 10,000 DNA lesions per cell per day (15).…”

mentioning

confidence: 99%

A DNA polymerase β mutant from colon cancer cells induces mutations

Lang

Maitra²,

Starcevic³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

124

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Previous investigations have shown that Ϸ35% of the 90 tumors analyzed to date contain mutations within the DNA polymerase ␤ (pol ␤) gene. The existence of pol ␤ mutations in a substantial fraction of human tumors studied suggests a link between DNA pol ␤ and cancer. A DNA pol ␤ variant, in which Lys-289 has been altered to Met, was identified previously in a colorectal carcinoma. The K289M protein was expressed in mouse L cells containing the cII mutational target. The DNA was packaged and used to infect bacterial cells to obtain the spontaneous mutation frequency. We found that expression of K289M in the mouse cells resulted in a 2.5-fold increase in the mutation frequency. What was most interesting was that expression of K289M in these cells resulted in a 16-fold increase in the frequency of C to G or G to C base substitutions at a specific site within the cII target. By using this cII target sequence, kinetic analysis of the purified K289M protein revealed that it was able to misincorporate dCTP opposite template C and dGTP opposite template G with significantly higher efficiency than the wild-type pol ␤ protein. We provide evidence that misincorporation of nucleotides by K289M results from altered positioning of the DNA within the active site of the enzyme. Our data are consistent with the interpretation that misincorporation of nucleotides resulting from altered DNA positioning by the K289M protein has the potential to result in tumorigenesis or neoplastic progression.M utations in the gene encoding DNA polymerase ␤ (pol ␤) have been identified in human colorectal, prostate, lung, and breast carcinomas and mouse lymphomas (1-5). Thus far, only 90 tumors have been analyzed for mutations within the pol ␤ coding sequence, and mutations are present in 35% of these tumors. The pol ␤ tumor-associated mutations are found only in the tumor, and not in normal tissue from the same patient, implying that they represent sporadic mutations underlying neoplastic disease. Furthermore, the mutations identified in these tumors are not present in the pol ␤ gene of 124 normal individuals (6). Also of interest is that pol ␤ is located within the proximal region of the short arm of chromosome 8 (p12-p11), a region that is frequently lost in a variety of human tumors, including colorectal and prostate carcinomas (7). These studies suggest a link between mutations within the pol ␤ gene and carcinogenesis. Another piece of evidence that is consistent with a role for pol ␤ in cancer is its interaction with the tumor suppressor protein p53 (8, 9). The p53 protein stabilizes pol ␤ at an abasic site. An alteration of the p53-pol ␤ interaction could result in less efficient DNA repair, which may contribute to the development of neoplastic disease. Most interestingly, a pol ␤ mutant with an 87-bp deletion, which has been found in primary colorectal, lung, and breast adenocarcinomas (3,5,10), is dominant to the WT enzyme and disrupts its base excision repair (BER) activity if expressed in human cell lines (11,12). It is quite possible t...

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“…Eukaryotic DNA polymerase ␤ (pol ␤) 1 is a nuclear DNA repair polymerase extensively characterized by Wilson (1,2). It mainly carries out gap filling during short patch base excision repair (3)(4)(5)(6)(7).…”

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confidence: 99%

Replication across O6-Methylguanine by Human DNA Polymerase β in Vitro

Singh

Snow

1996

Journal of Biological Chemistry

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Replication in vivo across unrepaired O 6 -methylguanine (m 6 dG) lesions by mammalian DNA polymerase ␤ (pol ␤) during short patch repair may contribute to the cytotoxicity and mutagenesis of m 6 dG. We have employed in vitro steady state kinetic analysis to investigate the replication of oligonucleotide templates containing site-specific m 6 dG by human pol ␤. Our results show that m 6 dG is a strong but not absolute block to replication by pol ␤. pol ␤ exhibits mixed kinetic discrimination during overall replication across dG and m 6 dG. pol ␤ preferentially inserts dTMP rather than dCMP opposite m 6 dG. However, pol ␤ extends from the dC-m 6 dG base pair more efficiently than from the dTm 6 dG base pair. This is in strong contrast to other polymerases such as the exonuclease-deficient Klenow fragment of Escherichia coli DNA polymerase I (exo ؊ KF) that preferentially extends dT-m 6 dG by a factor of 10 over dC-m 6 dG. When both insertion and extension are considered, pol ␤ has a 15-fold overall preference for incorporation of the mutagenic substrate dTTP rather than the nonmutagenic substrate dCTP during replication across m 6 dG. This suggests that pol ␤, in concert with the T:G-specific thymine DNA glycosylase, may be intricately involved in the futile cytotoxic repair induced by m 6 dG. Our results also suggest that replication across m 6 dG by pol ␤ may contribute to m 6 dG-induced G 3 A transition mutations.1 is a nuclear DNA repair polymerase extensively characterized by Wilson (1, 2). It mainly carries out gap filling during short patch base excision repair (3-7). pol ␤ fills short (up to six nucleotides long) DNA gaps (4 -8) and has been found to act in concert with uracil glycosylase (3) and the human G:T-specific thymine glycosylase (9). pol ␤ is also implicated in the repair of DNA damage induced by anticancer agents such as bleomycin, ␥-irradiation (10), cisplatin (11), and alkylating agents (12). Resistance to cisplatin may be partially due to overexpression of pol ␤ (11). Tumors may also develop resistance to radiation therapy and chemotherapy (e.g. cisplatin and alkylating agents) by increased efficiency of DNA repair. pol ␤ has been found to be altered in some human cancers (13,14), suggesting its importance in maintaining genomic stability. However, pol ␤ is the most error prone of all known polymerases tested in vitro (15).Mechanistic studies of pol ␤ are important for understanding its diverse roles in DNA replication and repair under circumstances leading to mutagenesis, cytotoxicity, tumor progression, and the resistance of tumors to anticancer therapy. Furthermore, the small size, single subunit composition, availability of crystal structure, and absence of confounding associated activities (such as 3Ј-5Ј exonuclease) make pol ␤ a good model for the study of DNA polymerase structure and function.O 6 -Methylguanine (m 6 dG) is a mutagenic and cytotoxic DNA adduct that can be formed in vivo by such diverse agents as tobacco smoke, methylnitrosourea, and other S n 1 methylating agents (16)....

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Progress toward molecular biology of DNA polymerase β

Cited by 51 publications

References 29 publications

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

A DNA polymerase β mutant from colon cancer cells induces mutations

Replication across O6-Methylguanine by Human DNA Polymerase β in Vitro

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