Skp2 E3 Ligase Integrates ATM Activation and Homologous Recombination Repair by Ubiquitinating NBS1

Juan Wu, Xian Zhang, Ling Zhang, Ching Yuan Wu, Abdol Hossein Rezaeian, Chia Hsin Chan, Ju Mei Li, Jing Wang, Yuan Gao, Fei Han, Yun Seong Jeong, Xiandao Yuan, Kum Kum Khanna, Jianping Jin, Yi Xin Zeng, Hui Kuan Lin

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

The Mre11/Rad50/NBS1 (MRN) complex is thought to be a critical sensor that detects damaged DNA and recruits ATM to DNA foci for activation. However, it remains to be established how the MRN complex regulates ATM recruitment to the DNA foci during DNA double-strand breaks (DSBs). Here we show that Skp2 E3 ligase is a key component for the MRN complex-mediated ATM activation in response to DSBs. Skp2 interacts with NBS1 and triggers K63-linked ubiquitination of NBS1 upon DSBs, which is critical for the interaction of NBS1 with ATM, thereby facilitating ATM recruitment to the DNA foci for activation. Finally, we show that . Skp2 deficiency exhibits a defect in homologous recombination (HR) repair, thereby increasing IR sensitivity. Our results provide molecular insights into how Skp2 and the MRN complex coordinate to activate ATM, and identify Skp2-mediatetd NBS1 ubiquitination as a vital event for ATM activation in response to DNA damage.

Original languageEnglish (US)
Pages (from-to)351-361
Number of pages11
JournalMolecular Cell
Volume46
Issue number3
DOIs
StatePublished - May 11 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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