Repair of Topoisomerase I-mediated DNA Damage.

This chapter discusses the use of inhibitors of tyrosyl-DNA phosphodiesterase (Tdp1) and Chk1/2 in combination with Topoisomerase I (TopI) inhibitors. TopI is an abundant and essential enzyme. It is the selective target of camptothecins, which are effective anticancer agents. TopI–DNA cleavage complexes can also be trapped by various endogenous and exogenous DNA lesions, including mismatches, abasic sites, and carcinogenic adducts. Tdp1 is one of the repair enzymes for Top1–DNA covalent complexes. It forms a multiprotein complex that includes poly (Adenosine diphosphate (ADP)–ribose) polymerase (PARP). PARP-deficient cells are hypersensitive to camptothecins and functionally deficient for Tdp1. This chapter reviews the developments in several pathways involved in the repair of Top1 cleavage complexes and the role of Chk1 and Chk2 checkpoint kinases in the cellular responses to Top1 inhibitors. The genes conferring camptothecin hypersensitivity are compiled for humans, budding yeast, and fission yeast.