Translesion DNA synthesis polymerases in DNA interstrand crosslink repair.
DNA interstrand crosslinks (ICLs) are induced by a number of bifunctional antitumor drugs such as cisplatin, mitomycin C, or the nitrogen mustards as well as endogenous agents formed by lipid peroxidation. The repair of ICLs requires the coordinated interplay of a number of genome maintenance pathways, leading to the removal of ICLs through at least two distinct mechanisms. The major pathway of ICL repair is dependent on replication, homologous recombination, and the Fanconi anemia (FA) pathway, whereas a minor, G0/G1-specific and recombination-independent pathway depends on nucleotide excision repair. A central step in both pathways in vertebrates is translesion synthesis (TLS) and mutants in the TLS polymerases Rev1 and Pol zeta are exquisitely sensitive to crosslinking agents. Here, we review the involvement of Rev1 and Pol zeta as well as additional TLS polymerases, in particular, Pol eta, Pol kappa, Pol iota, and Pol nu, in ICL repair. Biochemical studies suggest that multiple TLS polymerases have the ability to bypass ICLs and that the extent ofbypass depends upon the structure as well as the extent of endo- or exonucleolytic processing of the ICL. As has been observed for lesions that affect only one strand of DNA, TLS polymerases are recruited by ubiquitinated proliferating nuclear antigen (PCNA) to repair ICLs in the G0/G1 pathway. By contrast, this data suggest that a different mechanism involving the FA pathway is operative in coordinating TLS in the context of replication-dependent ICL repair.
Ho
The Vinh
TV
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794-3400, USA.
Schärer
Orlando D
OD
D000818:Animals; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis*; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular
D003432:Cross-Linking Reagents; D004247:DNA; D004259:DNA-Directed DNA Polymerase