Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 12, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2022600118
Keywords
DNA end resection; homologous recombination; CtIP; ATM; hyperphosphorylation
Categories
Funding
- National Natural Science Foundation of China [31971220, 31730021, 31700715, 31961160725]
- National Key Research and Development Program of China [2018YFC2000100, 2018YFC1004900]
- Fok Ying Tung Education Foundation
- China's Fundamental Research Funds for the Central Universities
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This study identifies a novel regulatory mechanism that modulates the activity of CtIP at DSBs and the extent of end resection through ATM-dependent sequential posttranslational modification of CtIP.
DNA end resection is a critical step in the repair of DNA double-strand breaks (DSBs) via homologous recombination (HR). However, the mechanisms governing the extent of resection at DSB sites undergoing homology-directed repair remain unclear. Here, we show that, upon DSB induction, the key resection factor CtIP is modified by the ubiquitin-like protein SUMO at lysine 578 in a PIAS4-dependent manner. CtIP SUMOylation occurs on damaged chromatin and requires prior hyperphosphorylation by the ATM protein kinase. SUMO-modified hyperphosphorylated CtIP is targeted by the SUMO-dependent E3 ubiquitin ligase RNF4 for polyubiquitination and subsequent degradation. Consequently, disruption of CtIP SUMOylation results in aberrant accumulation of CtIP at DSBs, which, in turn, causes uncontrolled excessive resection, defective HR, and increased cellular sensitivity to DSB-inducing agents. These findings reveal a previously unidentified regulatory mechanism that regulates CtIP activity at DSBs and thus the extent of end resection via ATM-dependent sequential posttranslational modification of CtIP.
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