14-3-3 Proteins restrain the Exo1 nuclease to prevent overresection

Xiaoqing Chen, In Kwon Kim, Yuchi Honaker, Sharad C. Paudyal, Won Kyun Koh, Melanie Sparks, Shan Li, Helen Piwnica-Worms, Tom Ellenberger, Zhongsheng You

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

The DNA end resection process dictates the cellular response to DNA double strand break damage and is essential for genome maintenance. Although insufficient DNA resection hinders homology-directed repair and ATR (ataxia telangiectasia and Rad3 related)-dependent checkpoint activation, overresection produces excessive single-stranded DNA that could lead to genomic instability. However, the mechanisms controlling DNA end resection are poorly understood. Here we show that the major resection nuclease Exo1 is regulated both positively and negatively by protein-protein interactions to ensure a proper level of DNA resection. We have shown previously that the sliding DNA clamp proliferating cell nuclear antigen (PCNA) associates with the C-terminal domain of Exo1 and promotes Exo1 damage association and DNA resection. In this report, we show that 14-3-3 proteins interact with a central region of Exo1 and negatively regulate Exo1 damage recruitment and subsequent resection. 14-3-3s limit Exo1 damage association, at least in part, by suppressing its association with PCNA. Disruption of the Exo1 interaction with 14-3-3 proteins results in elevated sensitivity of cells to DNA damage. Unlike Exo1, the Dna2 resection pathway is apparently not regulated by PCNA and 14-3-3s. Our results provide critical insights into the mechanism and regulation of the DNA end resection process and may have implications for cancer treatment.

Original languageEnglish
Pages (from-to)12300-12312
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number19
DOIs
StatePublished - May 8 2015

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