Evidence for base excision repair processing of DNA interstrand crosslinks

Abstract

Many bifunctional alkylating agents and anticancer drugs exert their cytotoxicity by producing cross links between the two complementary strands of DNA, termed interstrand crosslinks (ICLs). This blocks the strand separating processes during DNA replication and transcription, which can lead to cell cycle arrest and apoptosis. Cells use multiple DNA repair systems to eliminate the ICLs. Concerted action of repair proteins involved in Nucleotide Excision Repair and Homologous Recombination pathways are suggested to play a key role in the ICL repair. However, recent studies indicate a possible role for Base Excision Repair (BER) in mediating the cytotoxicity of ICL inducing agents in mammalian cells. Elucidating the mechanism of BER mediated modulation of ICL repair would help in understanding the recognition and removal of ICLs and aid in the development of potential therapeutic agents. In this review, the influence of BER proteins on ICL DNA repair and the possible mechanisms of action are discussed.

Quantification of DNA interstrand crosslinks induced by ACNU in NIH/3T3 and L1210 cells using high-performance liquid chromatography/electrospray ionization tandem mass spectrometry

“…The decrease in the crosslinking level is also possibly due to death of the cells containing high levels of DNA damage. Moreover, besides the AGT‐mediated repair mechanism, there are other pathways repairing the crosslinked base pair, such as the base excision repair (BER) processing, in which the BER proteins are capable of recognizing and removing the crosslinked base pairs induced by chemotherapeutic agents …”

“…Moreover, besides the AGT-mediated repair mechanism, there are other pathways repairing the crosslinked base pair, such as the base excision repair (BER) processing, in which the BER proteins are capable of recognizing and removing the crosslinked base pairs induced by chemotherapeutic agents. [41] Ueda-Kawamitsu et al [14] performed a quantitative analysis of BCNU-induced dG-dC crosslinks in L1210 leukemia cells by fluorescence assay with BCNU exposure for 24 h. The results indicated that the maximum level of DNA ICL was observed at 6 h followed by a decline, which was attributed to the repair mechanism. Both of the two studies gave direct evidence for the AGT-mediated repair of DNA ICLs by observing obvious decreases in the crosslinking levels, although different peak times of the crosslinking levels were observed.…”

A role for the base excision repair enzyme NEIL3 in replication-dependent repair of interstrand DNA cross-links derived from psoralen and abasic sites

“…In another set of studies, it was found that the deletion of the BER proteins Pol β and uracil DNA glycosylase (UNG) conferred resistance to cisplatin toxicity [90]. This led to a proposal that UNGs remove uracil residues generated by deamination of cytosine residues near cisplatin cross-links, thus inhibiting subsequent repair [91]. In a final early example where BER may influence the repair of cross-links, Couvé et al showed that NEIL1 can excise an unhooked, psoralen-derived cross-link remnant from a three-stranded structure (e.g.…”

Differential role of base excision repair proteins in mediating cisplatin cytotoxicity

“…However, in the case of ovarian cancer, no significant difference was found between APE1 expression in platinum sensitive and platinum refractory cancers [9]. Targeting APE1 has been shown to mediate sensitivity to DNA damaging agents such as BCNU and MMC [10, 11]. Accumulation of abasic sites and subsequent generation of DNA double strand breaks (DSBs) are likely responsible for this cellular sensitivity.…”