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

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 Sk...

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Bibliographic Details
Published in:Molecular cell 2012-05, Vol.46 (3), p.351-361
Main Authors: Wu, Juan, Zhang, Xian, Zhang, Ling, Wu, Ching-Yuan, Rezaeian, Abdol Hossein, Chan, Chia-Hsin, Li, Ju-Mei, Wang, Jing, Gao, Yuan, Han, Fei, Jeong, Yun Seong, Yuan, Xiandao, Khanna, Kum Kum, Jin, Jianping, Zeng, Yi-Xin, Lin, Hui-Kuan
Format: Article
Language:English
Subjects:
Animals
Ataxia Telangiectasia Mutated Proteins
Cell Cycle Proteins - metabolism
Cell Line, Tumor
DNA
DNA Damage
DNA repair
DNA-Binding Proteins - metabolism
HEK293 Cells
HeLa Cells
homologous recombination
Humans
Mice
Models, Genetic
Nuclear Proteins - metabolism
Protein-Serine-Threonine Kinases - metabolism
Recombinational DNA Repair
S-Phase Kinase-Associated Proteins - genetics
S-Phase Kinase-Associated Proteins - metabolism
S-Phase Kinase-Associated Proteins - physiology
Tumor Suppressor Proteins - metabolism
ubiquitin-protein ligase
Ubiquitination
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Summary: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. [Display omitted] ▸ Skp2 E3 ligase is critical for ATM activation in response to IR ▸ Skp2 interacts with the MRN complex and triggers K63-linked ubiquitination of NBS1 ▸ NBS1 ubiquitination regulates NBS1 and ATM interaction ▸ ATM and Skp2 regulate HR repair
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2012.02.018