Coordinated nuclease activities counteract Ku at single-ended DNA double-strand breaks

Pauline Chanut, Sébastien Britton (), Julia Coates, Stephen P. Jackson () and Patrick Calsou ()
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Pauline Chanut: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS
Sébastien Britton: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS
Julia Coates: The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge
Stephen P. Jackson: The Wellcome Trust and Cancer Research UK Gurdon Institute, University of Cambridge
Patrick Calsou: Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Repair of single-ended DNA double-strand breaks (seDSBs) by homologous recombination (HR) requires the generation of a 3′ single-strand DNA overhang by exonuclease activities in a process called DNA resection. However, it is anticipated that the highly abundant DNA end-binding protein Ku sequesters seDSBs and shields them from exonuclease activities. Despite pioneering works in yeast, it is unclear how mammalian cells counteract Ku at seDSBs to allow HR to proceed. Here we show that in human cells, ATM-dependent phosphorylation of CtIP and the epistatic and coordinated actions of MRE11 and CtIP nuclease activities are required to limit the stable loading of Ku on seDSBs. We also provide evidence for a hitherto unsuspected additional mechanism that contributes to prevent Ku accumulation at seDSBs, acting downstream of MRE11 endonuclease activity and in parallel with MRE11 exonuclease activity. Finally, we show that Ku persistence at seDSBs compromises Rad51 focus assembly but not DNA resection.

Date: 2016
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DOI: 10.1038/ncomms12889

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