A conserved Ctp1/CtIP C-terminal peptide stimulates Mre11 endonuclease activity

Aleksandar Zdravković, James M. Daley, Arijit Dutta, Tatsuya Niwa, Yasuto Murayama, Shuji Kanamaru, Kentaro Ito, Takahisa Maki, Bilge Argunhan, Masayuki Takahashi, Hideo Tsubouchi, Patrick Sung, Hiroshi Iwasaki

Research output: Contribution to journalArticlepeer-review

Abstract

The Mre11-Rad50-Nbs1 complex (MRN) is important for repairing DNA double-strand breaks (DSBs) by homologous recombination (HR). The endonuclease activity of MRN is critical for resecting 5′- ended DNA strands at DSB ends, producing 3′-ended single-strand DNA, a prerequisite for HR. This endonuclease activity is stimulated by Ctp1, the Schizosaccharomyces pombe homolog of human CtIP. Here, with purified proteins, we show that Ctp1 phosphorylation stimulatesMRN endonuclease activity by inducing the association of Ctp1 with Nbs1. The highly conserved extreme C terminus of Ctp1 is indispensable for MRN activation. Importantly, a polypeptide composed of the conserved 15 amino acids at the C terminus of Ctp1 (CT15) is sufficient to stimulate Mre11 endonuclease activity. Furthermore, the CT15 equivalent from CtIP can stimulate human MRE11 endonuclease activity, arguing for the generality of this stimulatory mechanism. Thus, we propose that Nbs1-mediated recruitment of CT15 plays a pivotal role in the activation of the Mre11 endonuclease by Ctp1/CtIP.

Original languageEnglish (US)
Article numbere2016287118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number11
DOIs
StatePublished - Mar 16 2021

Keywords

  • Ctp1/CtIP
  • Double-strand break repair
  • Fission yeast
  • Homologous recombination
  • Mre11-Rad50-Nbs1

ASJC Scopus subject areas

  • General

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