DNA repair factor MRE11/RAD50 cleaves 3'-phosphotyrosyl bonds and resects DNA to repair damage caused by topoisomerase 1 poisons.
MRE11-RAD50 is a highly conserved multifunctional DNA repair factor. Here, we show that MRE11-RAD50 cleaves the covalent 3'-phosphotyrosyl-DNA bonds that join topoisomerase 1 (Top1) to the DNA backbone and that are the hallmark of damage caused by Top1 poisons such as camptothecin. Cleavage generates a 3'-phosphate DNA end that MRE11-RAD50 can resect in an ATP-regulated reaction, to produce a 3'-hydroxyl that can prime repair synthesis. The 3'-phosphotyrosyl cleavage activity maps to the MRE11 active site. These results define a new activity of MRE11 and distinguish MRE11-RAD50 functions in repair of Top1-DNA complexes and double-strand breaks.
Department of Immunology, University of Washington, Seattle, Washington 98195, USA.
Elizabeth J
EJ
Sacho
Nancy
N
Maizels
D019843:Archaeal Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D002166:Camptothecin / Q000737:chemistry*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D020027:Pyrococcus furiosus / Q000737:chemistry* / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000737:chemistry*
D019843:Archaeal Proteins; D004268:DNA-Binding Proteins; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin