The E295K DNA Polymerase Beta Gastric Cancer-Associated Variant Interferes with Base Excision Repair and Induces Cellular Transformation

Lang, Tieming; Dalal, Shibani; Chikova, Anna; DiMaio, Daniel; Sweasy, Joann B.

doi:10.1128/mcb.01883-06

Cited by 92 publications

(153 citation statements)

References 40 publications

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“…Leu22Pro tumor-associated variant of polβ is dRP lyase deficient (Dalal et al, 2008). It is being reported that the E295K mutation in polβ which is a gastric cancer-associated variant interferes with base excision repair and induces cellular transformation (Lang et al, 2007). Therefore, any kind of point mutation or large deletion can change the conformation during the polymerase opening and thereby altering the DNA positioning in the active site (Yang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The Val246 variant was shown to mis-incorporate nucleotides through altered DNA positioning in the active site (Dalal et al, 2008). It was evidenced that expression of the E295K gastric carcinoma-associated pol beta variant (Lang et al, 2007) in mouse cells interferes with BER and induces sister chromatid exchanges and cellular transformation (Lang et al, 2007). An 87-bp deletion variant of polβ that has been found to be associated with breast, lung (Bhattacharyya and Banerjee 1997;Bhattacharyya et al, 1999a), colon, kidney, prostate cancer, has been shown to act as a dominant negative mutant (Bhattacharyya et al, 1999;Chen et al, 2000;Bhattacharyya et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ_{63-123, 208-304}) with the Risk Factor of Ovarian Carcinoma in India

Khanra

Bhattacharya²,

Bhattacharyya³

2012

Asian Pacific Journal of Cancer Prevention

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ_{63-123, 208-304}) with the Risk Factor of Ovarian Carcinoma in India

Khanra

Bhattacharya²,

Bhattacharyya³

2012

Asian Pacific Journal of Cancer Prevention

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“…Data represent the mean of three independent experiments with error bars showing SEM. (B and C) Base excision repair assays of MEF cell extracts using either a Uracil (B) or hypoxanthine (C) substrate as described previously (12). BER assays were carried out as described in Experimental Procedures.…”

Section: Discussionmentioning

confidence: 99%

“…MEF extracts were prepared as described previously, and base excision repair assays were conducted with either a UDG or hypoxanthine substrate as described previously (12). BER reactions were quenched by addition of an equal volume of formamide gel loading dye [90% (vol/vol) formamide, 0.3 M EDTA].…”

Section: Methodsmentioning

confidence: 99%

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Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates

Senejani

Dalal

Liu

et al. 2012

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

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DNA is susceptible to damage by a wide variety of chemical agents that are generated either as byproducts of cellular metabolism or exposure to man-made and harmful environments. Therefore, to maintain genomic integrity, having reliable DNA repair systems is important. DNA polymerase β is known to be a key player in the base excision repair pathway, and mice devoid of DNA polymerase beta do not live beyond a few hours after birth. In this study, we characterized mice harboring an impaired pol β variant. This Y265C pol β variant exhibits slow DNA polymerase activity but WT lyase activity and has been shown to be a mutator polymerase. Mice expressing Y265C pol β are born at normal Mendelian ratios. However, they are small, and 60% die within a few hours after birth. Slow proliferation and significantly increased levels of cell death are observed in many organs of the E14 homozygous embryos compared with WT littermates. Mouse embryo fibroblasts prepared from the Y265C pol β embryos proliferate at a rate slower than WT cells and exhibit a gap-filling deficiency during base excision repair. As a result of this, chromosomal aberrations and single-and double-strand breaks are present at significantly higher levels in the homozygous mutant versus WT mouse embryo fibroblasts. This is study in mice is unique in that two enzymatic activities of pol β have been separated; the data clearly demonstrate that the DNA polymerase activity of pol β is essential for survival and genome stability. Thus, having a reliable DNA repair system is crucial to maintain the integrity of cellular DNA (1-3). DNA polymerase beta (pol β) is a 39-kDa protein (4) that is a member of the X family group of DNA polymerases. pol β is a key player in base excision repair (BER) (4-6). During BER, damaged bases are recognized and excised by lesion-specific DNA glycosylases (7). Subsequently, the DNA backbone is cleaved by AP endonuclease (APE1), creating 3′-OH and 5′-deoxyribose phosphate (5′-dRP) ends. pol β, the major polymerase during BER, fills in the gap by adding nucleotide/s onto the 3′-OH using polymerase activity, and removes the 5′-dRP group using its lyase activity. The nick is then sealed by XRCC1-DNA ligase IIIα (8). For oxidative damage, bifunctional glycosylases play a major role and cleave the backbone. The DNA ends are remodeled by phosphatases or phosphodiesterases (9) before pol β fills in the gap. Therefore, pol β functions in the gapfilling step of all short-patch BER subpathways.Results from small-scale studies have shown that about one third of all human tumors express pol β variant proteins (10). We have shown that some of these tumor-associated variant forms of pol β can induce a mutator phenotype and chromosomal aberrations by either error-prone or slow gap filling, respectively (10-12). The Y265C pol β variant was identified in a gastric carcinoma and has been shown to be a strong mutator polymerase, both in vitro and in vivo (13,14). In murine LN12 cells, expression of Y265C leads to an eightfold increase in mutation frequency...

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DNA repair and personalized breast cancer therapy

Sjolund

Harris

et al. 2010

Environ and Mol Mutagen

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Personalized cancer therapy is likely to be one of the next big advances in our search for a cure for cancer. To be able to treat people in an individualized manner, researchers need to know a great deal about their genetic constitution and the DNA repair status of their tumors. Specific knowledge is required regarding the polymorphisms individuals carry and how these polymorphisms influence responses to therapy. Researchers are actively engaged in biomarker discovery and validation for this purpose. In addition, the design of clinical trials must be reassessed to include new information on biomarkers and drug responses. In this review, we focus on personalized breast cancer therapy. The hypothesis we focus upon in this review is that there is connection between the DNA repair profile of individuals, their breast tumor subtypes, and their responses to cancer therapy. We first briefly review cellular DNA repair pathways that are likely to be impacted by breast cancer therapies. Next, we review the phenotypes of breast tumor subtypes with an emphasis on how a DNA repair deficiency might result in tumorigenesis itself and lead to the chemotherapeutic responses that are observed. Specific examples of breast tumor subtypes and their responses to cancer therapy are given, and we discuss possible DNA repair mechanisms that underlie the responses of tumors to various chemotherapeutic agents. Much is known about breast cancer subtypes and the way each of these subtypes responds to chemotherapy. In addition, we discuss novel design of clinical trials that incorporates rapidly emerging information on biomarkers.

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The E295K DNA Polymerase Beta Gastric Cancer-Associated Variant Interferes with Base Excision Repair and Induces Cellular Transformation

Cited by 92 publications

References 40 publications

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ_{63-123, 208-304}) with the Risk Factor of Ovarian Carcinoma in India

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ_{63-123, 208-304}) with the Risk Factor of Ovarian Carcinoma in India

Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates

DNA repair and personalized breast cancer therapy

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The E295K DNA Polymerase Beta Gastric Cancer-Associated Variant Interferes with Base Excision Repair and Induces Cellular Transformation

Cited by 92 publications

References 40 publications

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ63-123, 208-304) with the Risk Factor of Ovarian Carcinoma in India

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ63-123, 208-304) with the Risk Factor of Ovarian Carcinoma in India

Y265C DNA polymerase beta knockin mice survive past birth and accumulate base excision repair intermediate substrates

DNA repair and personalized breast cancer therapy

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Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ_{63-123, 208-304}) with the Risk Factor of Ovarian Carcinoma in India

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ_{63-123, 208-304}) with the Risk Factor of Ovarian Carcinoma in India