Enhanced expression and activity of DNA polymerase β in human ovarian tumor cells: impact on sensitivity towards antitumor agents

Bergoglio, Valérie; Canitrot, Yvan; Hogarth, Linda; Minto, Lynne; Howell, Stephen B.; Cazaux, Christophe; Hoffmann, Jean-Sébastien

doi:10.1038/sj.onc.1204743

Cited by 79 publications

(64 citation statements)

References 29 publications

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“…We previously demonstrated that overexpression of Pol b in cells resulted also in a highly mutagenic tolerance phenotype to bifunctional cross-linking agents used in cancer chemotherapy such as cisplatin, melphalan, and mechlorethamine by facilitating the bypass replication process of the associated adducts, suggesting that the enzyme may have a role in tumor progression during chemotherapy (Canitrot et al, 1998). Inversely, we found that a deregulation of Pol b rendered the cells hypersensitive to the cytotoxic action of antimetabolites used in chemotherapy such as Ara-C (unpublished data) or 6-TG by facilitating the incorporation of the triphosphorylated forms of these analogs into DNA (Bergoglio et al, 2001). We addressed here the question of the potential implication of excess Pol b directly in response to another major therapeutic source, the ionizing radiations, which are known to induce a variety of DNA lesions, through the formation of excited and ionized molecules, including damage to nucleotide bases, cross-linking, and DNA single-and double-strand breaks (DSBs).…”

Section: Introductionmentioning

confidence: 79%

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

et al. 2002

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is an error-prone enzyme which has been found to be overexpressed in several human tumors. By using a couple of recombinant CHO cells di ering only from the exogenous expression of Pol b b, we showed here that cells overexpressing Pol b b are much more sensitive to IR treatments by increasing apoptosis. We also found that the surviving cells displayed an hypermutator phenotype which could be explained by di erent pathways involving Pol b b, such as (i) an increased capacity to incorporate into DNA the mutagenic dGTP analog, 8-oxo-dGTP, one of the most abundant purine-derived nucleotides exposed to g girradiation, (ii) the induction of IR-induced DNA breaks and (iii) accumulation of chromosome aberrations induced by radiation. Alteration of Pol b b expression in irradiated cells thus appears to strengthen both cell death and genetic changes associated with a malignant phenotype. These data provide new insights into the cellular response to radiations and the associated carcinogenic consequences.

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Section: Introductionmentioning

confidence: 79%

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

et al. 2002

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“…Significant efforts have also been made in identifying the role of BER in cisplatin cytotoxicity. Pol␤ and APE1 are overexpressed in various cancer cells, which relates to cisplatin resistance (11,16). Overexpression of Pol␤ leads to bifunctional DNA damage tolerance and facilitates the error-prone translesion synthesis over the adducts that otherwise would block DNA replication and kill the cells (14,36).…”

Section: Discussionmentioning

confidence: 99%

“…The involvement of BER has also been demonstrated in the lesion bypass of cisplatin DNA adducts (14,15). This has clinical relevance as many cancer types have been shown to have deregulated BER protein levels (11,16,17). An Oncomine TM (Compendia Bioscience, Ann Arbor, MI) search revealed that cisplatin-resistant cells display enhanced as well as reduced expression of BER proteins in tumor samples and cancer cells.…”

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Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

Kothandapani

Dangeti

Brown

et al. 2011

Journal of Biological Chemistry

121

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Using isogenic mouse embryonic fibroblasts and human cancer cell lines, we show that cells defective in base excision repair (BER) display a cisplatin-specific resistant phenotype. This was accompanied by enhanced repair of cisplatin interstrand crosslinks (ICLs) and ICL-induced DNA double strand breaks, but not intrastrand adducts. Cisplatin induces abasic sites with a reduced accumulation in uracil DNA glycosylase (UNG) null cells. We show that cytosines that flank the cisplatin ICLs undergo preferential oxidative deamination in vitro, and AP endonuclease 1 (APE1) can cleave the resulting ICL DNA substrate following removal of the flanking uracil. We also show that DNA polymerase ␤ has low fidelity at the cisplatin ICL site after APE1 incision. Down-regulating ERCC1-XPF in BER-deficient cells restored cisplatin sensitivity. Based on our results, we propose a novel model in which BER plays a positive role in maintaining cisplatin cytotoxicity by competing with the productive cisplatin ICL DNA repair pathways.

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“…Early observations indicated that Pol b is highly expressed in several cancer cell lines grown in vitro (Canitrot et al, 1999;Srivastava et al, 1999;Bergoglio et al, 2001). More recently, Albertella et al (2005) found that Pol b was overexpressed twofold or greater at the mRNA and protein levels in approximately one-third of all the tumors sampled compared with normal tissues, notably in 40% of colon cancer and two out of three malignant melanoma cases studied.…”

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confidence: 99%

Cells deficient in the base excision repair protein, DNA polymerase beta, are hypersensitive to oxaliplatin chemotherapy

et al. 2009

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A significant proportion of human cancers overexpress DNA polymerase beta (Pol b), the major DNA polymerase involved in base excision repair. The underlying mechanism and biological consequences of overexpression of this protein are unknown. We examined whether Pol b, expressed at levels found in tumor cells, is involved in the repair of DNA damage induced by oxaliplatin treatment and whether the expression status of this protein alters the sensitivity of cells to oxaliplatin. DNA damage induced by oxaliplatin treatment of HCT116 and HT29 colon cancer cells was observed to be associated with the stabilization of Pol b protein on chromatin. In comparison with HCT116 colon cancer cells, isogenic oxaliplatin-resistant (HCT-OR) cells were found to have higher constitutive levels of Pol b protein, faster in vitro repair of a DNA substrate containing a single nucleotide gap and faster repair of 1,2-GG oxaliplatin adduct levels in cells. In HCT-OR cells, small interfering RNA knockdown of Pol b delayed the repair of oxaliplatin-induced DNA damage. In a different model system, Pol b-deficient fibroblasts were less able to repair 1,2-GG oxaliplatin adducts and were hypersensitive to oxaliplatin treatment compared with isogenic Pol b-expressing cells. Consistent with previous studies, Pol b-deficient mouse fibroblasts were not hypersensitive to cisplatin treatment. These data provide the first link between oxaliplatin sensitivity and DNA repair involving Pol b. They demonstrate that Pol b modulates the sensitivity of cells to oxaliplatin treatment.

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Enhanced expression and activity of DNA polymerase β in human ovarian tumor cells: impact on sensitivity towards antitumor agents

Cited by 79 publications

References 29 publications

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities

Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

Cells deficient in the base excision repair protein, DNA polymerase beta, are hypersensitive to oxaliplatin chemotherapy

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