Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 22, Issue 2, Pages 150-157Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2937
Keywords
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Funding
- Wellcome Trust
- Cancer Research UK (CRUK) [C6/A11224]
- European Research Council
- European Community Seventh Framework Programme [HEALTH-F2-2010-259893]
- Cancer Research UK [C6946/A14492]
- Wellcome Trust [WT092096]
- University of Cambridge
- Ataxia Telangiectasia Society
- Cancer Research UK [18796, 11224] Funding Source: researchfish
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Mammalian CtIP protein has major roles in DNA double-strand break (DSB) repair. Although it is well established that CtIP promotes DNA-end resection in preparation for homology-dependent DSB repair, the molecular basis for this function has remained unknown. Here we show by biophysical and X-ray crystallographic analyses that the N-terminal domain of human CtIP exists as a stable homotetramer. Tetramerization results from interlocking interactions between the N-terminal extensions of CtIP's coiled-coil region, which lead to a 'dimer-of-dimers' architecture. Through interrogation of the CtIP structure, we identify a point mutation that abolishes tetramerization of the N-terminal domain while preserving dimerization in vitro. Notably, we establish that this mutation abrogates CtIP oligomer assembly in cells, thus leading to strong defects in DNA-end resection and gene conversion. These findings indicate that the CtIP tetramer architecture described here is essential for effective DSB repair by homologous recombination.
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