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- Title
CtIP tetramer assembly is required for DNA-end resection and repair.
- Authors
Davies, Owen R; Forment, Josep V; Sun, Meidai; Belotserkovskaya, Rimma; Coates, Julia; Galanty, Yaron; Demir, Mukerrem; Morton, Christopher R; Rzechorzek, Neil J; Jackson, Stephen P; Pellegrini, Luca
- 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.
- Subjects
X-ray crystallography; DNA restriction enzymes; N-terminal residues; HOMOLOGOUS chromosomes; GENE conversion; DIMERIZATION; POINT mutation (Biology)
- Publication
Nature Structural & Molecular Biology, 2015, Vol 22, Issue 2, p150
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb.2937