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CtIP tetramer assembly is required for DNA-end resection and repair

Lookup NU author(s): Dr Owen Davies

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Abstract

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.


Publication metadata

Author(s): Davies OR, Forment JV, Sun M, Belotserkovskaya R, Coates J, Galanty Y, Demir M, Morton CR, Rzechorzek NJ, Jackson SP, Pellegrini L

Publication type: Article

Publication status: Published

Journal: Nature Structural and Molecular Biology

Year: 2015

Volume: 22

Pages: 150-157

Print publication date: 09/02/2015

Online publication date: 05/01/2015

Acceptance date: 21/11/2014

ISSN (print): 1545-9993

ISSN (electronic): 1545-9985

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/nsmb.2937

DOI: 10.1038/nsmb.2937


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