Repair of DNA-protein cross-links in mammalian cells

DNA-protein cross-links are generated by both endogenous and exogenous DNA damaging agents, as intermediates during normal DNA metabolism, and during abortive base excision repair. Cross-links are relatively common lesions that are lethal when they block progression of DNA polymerases. DNA-protein cross-links may be broadly categorized into four groups by the DNA and protein chemistries near the cross-link and by the source of the cross-link: DNA-protein cross-links may be found ( 1) in nicked DNA at the 3' end of one strand ( topo I), ( 2) in nicked DNA at the 5' end of one strand (pol beta), ( 3) at the 5' ends of both strands adjacent to nicks in close proximity ( topo II; Spo 11), and ( 4) in one strand of duplex DNA ( UV irradiation; bifunctional carcinogens and chemotherapeutic agents). Repair mechanisms are reasonably well-defined for groups 1 and 3, and suggested for groups 2 and 4. Our work is focused on the recognition and removal of DNA- protein cross-links in duplex DNA ( group 4).