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

Abstract

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.

Prognostic and Predictive Role of JWA and XRCC1 Expressions in Gastric Cancer

“…Moreover, JWA was shown to play a role in transcriptional and translational regulation of XRCC1 levels (18). XRCC1 is a critical component of the BER pathway, and downregulation of BER sensitized cancer to cisplatin or oxaliplatin (32,33). XRCC1 is also involved in NER (34), homologous recombination, and nonhomologous end joining (35,36), which are involved in platinum resistance (31).…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…Experimental evidence has linked expression levels of Pol-b, a key component of the BER pathway, to resistance to oxaliplatin across a panel of different cell lines, 207 but so far we lack data from clinical studies. BER however has an important role with respect to so-called 'synthetic lethality' through PARP inhibition; this topic is discussed below with respect to HRR.…”

Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance

“…The role in bypassing oxaliplatin-induced adducts in human DNA by DNA polymerases b, g, and h has also been postulated as a resistance mechanism. For example, overexpression of Polb-the major DNA polymerase involved in BER-or polh has been shown to confer resistance to oxaliplatin in colon and gastric cell lines, respectively (45,46). More recently, it has been observed that REV1 and Polz have a role in promoting both translesion DNA synthesis and DNA repair of damaged DNA after exposure to different platinum drugs, including oxaliplatin and in promoting resistance to these agents (47).…”