Journal
PLOS GENETICS
Volume 8, Issue 11, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003050
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Funding
- National Institutes of Health (NIH) [R01CA095114]
- NIH/NCI Ruth L. Kirschstein National Research Service Award [F32 CA128399]
- U.S. Air force grant [AFOSR FA9550-08-1-0384]
- Beckman Laser Institute Foundation, Irvine, California
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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, gamma H2AX, and phosphorylated ATM at sites of laser generated ICLs. In contrast, the appearance of gamma H2AX 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.
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