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Mol Cell. 2014 Jun 19;54(6):1012-21. doi: 10.1016/j.molcel.2014.04.012. Epub 2014 May 15.

CtIP maintains stability at common fragile sites and inverted repeats by end resection-independent endonuclease activity.

Author information

1
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
2
The Institute of Engineering in Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
3
Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
4
Biotechnology Core Laboratory, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
5
The Institute of Engineering in Medicine, University of California at San Diego, La Jolla, CA 92093, USA; Department of Biomedical Engineering, Beckman Laser Institute, University of California at Irvine, Irvine, CA 92612, USA.
6
Department of Radiation Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
7
Department of Pathology, Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
8
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: xiaohwu@scripps.edu.

Abstract

Chromosomal rearrangements often occur at genomic loci with DNA secondary structures, such as common fragile sites (CFSs) and palindromic repeats. We developed assays in mammalian cells that revealed CFS-derived AT-rich sequences and inverted Alu repeats (Alu-IRs) are mitotic recombination hotspots, requiring the repair functions of carboxy-terminal binding protein (CtBP)-interacting protein (CtIP) and the Mre11/Rad50/Nbs1 complex (MRN). We also identified an endonuclease activity of CtIP that is dispensable for end resection and homologous recombination (HR) at I-SceI-generated "clean" double-strand breaks (DSBs) but is required for repair of DSBs occurring at CFS-derived AT-rich sequences. In addition, CtIP nuclease-defective mutants are impaired in Alu-IRs-induced mitotic recombination. These studies suggest that an end resection-independent CtIP function is important for processing DSB ends with secondary structures to promote HR. Furthermore, our studies uncover an important role of MRN, CtIP, and their associated nuclease activities in protecting CFSs in mammalian cells.

PMID:
24837675
PMCID:
PMC4105207
DOI:
10.1016/j.molcel.2014.04.012
[Indexed for MEDLINE]
Free PMC Article

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