title: CtIP is required to initiate replication-dependent interstrand crosslink repair.
abstract: DNA interstrand crosslinks (ICLs) are toxic lesions that block the progression of replication and transcription. CtIP is a conserved DNA repair protein that facilitates DNA end resection in the double-strand break (DSB) repair pathway. Here we show that CtIP plays a critical role during initiation of ICL processing in replicating human cells that is distinct from its role in DSB repair. CtIP depletion sensitizes human cells to ICL inducing agents and significantly impairs the accumulation of DNA damage response proteins RPA, ATR, FANCD2, γH2AX, and phosphorylated ATM at sites of laser generated ICLs. In contrast, the appearance of γH2AX and phosphorylated ATM at sites of laser generated double strand breaks (DSBs) is CtIP-independent. We present a model in which CtIP functions early in ICL repair in a BRCA1- and FANCM-dependent manner prior to generation of DSB repair intermediates.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America. mlduquette@ucsd.edu
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Duquette
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Zhu
authors.forename: Ewan R
authors.initials: ER
authors.lastname: Taylor
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Tsay
authors.forename: Linda Z
authors.initials: LZ
authors.lastname: Shi
authors.forename: Michael W
authors.initials: MW
authors.lastname: Berns
authors.forename: Clare H
authors.initials: CH
authors.lastname: McGowan
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004706:Endodeoxyribonucleases; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D028022:Low-Level Light Therapy; D053858:Metabolic Networks and Pathways; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D002352:Carrier Proteins; D052236:Fanconi Anemia Complementation Group D2 Protein; C468783:H2AX protein, human; D006657:Histones; D009687:Nuclear Proteins; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human