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.

Figure 1

Differential processing of ICLs by BER. A. BER processing of cisplatin ICL. The cytosines adjacent to the cisplatin ICL are extrahelical and flipped away from the double helix. The extrahelical cytosines are more susceptible to oxidative deamination and can convert to uracils. If cytosine deamination occurs, UNG initiates BER at the cisplatin ICL site by excising uracil from the DNA creating an abasic site. This is followed by Ape1 incision and Polβ mediated gap filling and synthesis. Polβ is shown to exhibit low fidelity at the cisplatin ICL site [77]. B. BER processing of psoralen ICL. NER may be involved in the initial recognition and incision of the psoralen ICLs by endonucleases. Translesion synthesis occurs across the unhooked ICLs where TLS polymerases bypass the ICL intermediate. NEIL1 initiates BER by excising the unhooked ICL remnant swinging out of the helix. Ape1 and Polβ complete the downstream BER processing [111].