title: Skp2 E3 ligase integrates ATM activation and homologous recombination repair by ubiquitinating NBS1.
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.
authors.affiliation: State Key Laboratory of Oncology in South China and Department of Experimental Research, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Ching-Yuan
authors.initials: CY
authors.lastname: Wu
authors.forename: Abdol Hossein
authors.initials: AH
authors.lastname: Rezaeian
authors.forename: Chia-Hsin
authors.initials: CH
authors.lastname: Chan
authors.forename: Ju-Mei
authors.initials: JM
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.forename: Fei
authors.initials: F
authors.lastname: Han
authors.forename: Yun Seong
authors.initials: YS
authors.lastname: Jeong
authors.forename: Xiandao
authors.initials: X
authors.lastname: Yuan
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059767:Recombinational DNA Repair; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D044786:S-Phase Kinase-Associated Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases