title: Mus81-mediated DNA cleavage resolves replication forks stalled by topoisomerase I-DNA complexes.
abstract: Deoxyribonucleic acid (DNA) topoisomerases are essential for removing the supercoiling that normally builds up ahead of replication forks. The camptothecin (CPT) Top1 (topoisomerase I) inhibitors exert their anticancer activity by reversibly trapping Top1-DNA cleavage complexes (Top1cc's) and inducing replication-associated DNA double-strand breaks (DSBs). In this paper, we propose a new mechanism by which cells avoid Top1-induced replication-dependent DNA damage. We show that the structure-specific endonuclease Mus81-Eme1 is responsible for generating DSBs in response to Top1 inhibition and for allowing cell survival. We provide evidence that Mus81 cleaves replication forks rather than excises Top1cc's. DNA combing demonstrated that Mus81 also allows efficient replication fork progression after CPT treatment. We propose that Mus81 cleaves stalled replication forks, which allows dissipation of the excessive supercoiling resulting from Top1 inhibition, spontaneous reversal of Top1cc, and replication fork progression.
authors: Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Marie
authors: M
authors: Regairaz
authors: Yong-Wei
authors: YW
authors: Zhang
authors: Haiqing
authors: H
authors: Fu
authors: Keli K
authors: KK
authors: Agama
authors: Nalini
authors: N
authors: Tata
authors: Surbhi
authors: S
authors: Agrawal
authors: Mirit I
authors: MI
authors: Aladjem
authors: Yves
authors: Y
authors: Pommier
mesh_terms: D002166:Camptothecin / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D053837:DNA Cleavage; D004249:DNA Damage; D004261:DNA Replication / Q000502:physiology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D004268:DNA-Binding Proteins; D059004:Topoisomerase I Inhibitors; D004720:Endonucleases; C498772:MUS81 protein, human; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin