Protecting stalled DNA replication forks from degradation by promiscuous nucleases is essential to prevent genomic instability, a major driving force of tumorigenesis. Several proteins commonly associated with the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) have been implicated in the stabilization of stalled forks. Human CtIP, in conjunction with the MRE11 nuclease complex, plays an important role in HR by promoting DSB resection. Here, we report an unanticipated function for CtIP in protecting reversed forks from degradation. Unlike BRCA proteins, which defend nascent DNA strands from nucleolytic attack by MRE11, we find that CtIP protects perturbed forks from erroneous over-resection by DNA2. Finally, we uncover functionally synergistic effects between CtIP and BRCA1 in mitigating replication-stress-induced genomic instability. Collectively, our findings reveal a DSB-resection- and MRE11-independent role for CtIP in preserving fork integrity that contributes to the survival of BRCA1-deficient cells.
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Univ Nebraska Med Ctr, Eppley Inst, Omaha, NE 68198 USA
Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE 68198 USAUniv Nebraska Med Ctr, Eppley Inst, Omaha, NE 68198 USA
Barger, Carter J.
Biswas, Kajal
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NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USAUniv Nebraska Med Ctr, Eppley Inst, Omaha, NE 68198 USA
Biswas, Kajal
Chee, Linda
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Univ Nebraska Med Ctr, Eppley Inst, Omaha, NE 68198 USA
Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE 68198 USAUniv Nebraska Med Ctr, Eppley Inst, Omaha, NE 68198 USA
Chee, Linda
Drapkin, Ronny
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Univ Penn, Perelman Sch Med, Penn Ovarian Canc Res Ctr, Philadelphia, PA 19104 USAUniv Nebraska Med Ctr, Eppley Inst, Omaha, NE 68198 USA
Drapkin, Ronny
Sharan, Shyam
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NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USAUniv Nebraska Med Ctr, Eppley Inst, Omaha, NE 68198 USA
Sharan, Shyam
Karpf, Adam R.
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Univ Nebraska Med Ctr, Eppley Inst, Omaha, NE 68198 USA
Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE 68198 USAUniv Nebraska Med Ctr, Eppley Inst, Omaha, NE 68198 USA