Mutation Research 532 (2003) 173–203 Review Repair of and checkpoint response to topoisomerase I-mediated DNA damage Yves Pommier ∗ , Christophe Redon, V. Ashutosh Rao, Jennifer A. Seiler, Olivier Sordet, Haruyuki Takemura, Smitha Antony, LingHua Meng, ZhiYong Liao, Glenda Kohlhagen, HongLiang Zhang, Kurt W. Kohn Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Building 37, Room 5068, NIH, Bethesda, MD 20892-4255, USA Received 28 June 2003; received in revised form 21 August 2003; accepted 21 August 2003 Abstract Topoisomerase I (Top1) catalyzes two transesterification reactions: single-strand DNA cleavage and religation that are normally coupled for the relaxation of DNA supercoiling in transcribing and replicating chromatin. A variety of endogenous DNA modifications, potent anticancer drugs and carcinogens uncouple these two reactions, resulting in the accumulation of Top1 cleavage complexes. Top1 cleavage complexes damage DNA and kill cells by generating replication-mediated DNA double-strand breaks (DSBs) and by stalling transcription complexes. The repair of Top1-mediated DNA lesions involves integrated pathways that are conserved from yeasts to humans. Top1-mediated DNA damage and cell cycle checkpoint responses can be studied biochemically and genetically in yeast and human cells with known genetic defects. Defects in these repair/checkpoint pathways, which promote tumor development, explain, at least in part, the selectivity of camptothecins and other Top1 inhibitors for cancer cells. © 2003 Elsevier B.V. All rights reserved. Keywords: Topoisomerase; Homologous recombination; Camptothecin; Tdp1; Mre11; ATM; ATR; BRCA1; BRCA2; RAD52; RAD51; RPA, DNA–PK; Cell cycle checkpoints 1. Introduction DNA topoisomerases exist in all living organisms. In humans, there are 6 topoisomerase genes coding for nuclear topoisomerase I (Top1), mitochondrial topoi- somerase I (Top1mt) [1], topoisomerases II  and , and topoisomerases III  and  (reviewed in [2,3]). Nuclear Top1 is essential for animals as knockout are not viable in flies [4] and mice [5]. Top1 is how- ever dispensable both in budding yeast Saccharomyces ∗ Corresponding author. Fax: +1-301-402-0752. E-mail address: pommier@nih.gov (Y. Pommier). cerevisiae (YSC) [6] and fission yeast Saccharomyces pombe (YSP) [7]. A critical function of Top1 is to re- lax supercoiled DNA in transcribing and replicating chromatin. Top1 may also play roles in DNA repair and recombinations [8,9]. DNA topoisomerases are the targets of antimicro- bial and anticancer drugs, and mammalian Top1 is the selective target of camptothecins [10–12]. Top1 cleavage complexes (see Section 2) are also produced by endogenous and exogenous DNA lesions (for re- view see [13]), including UV-induced base modifica- tions, guanine methylation and oxidation, polycyclic aromatic carcinogenic adducts [14], base mismatches, 0027-5107/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.mrfmmm.2003.08.016