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

doi:10.1016/j.molcel.2012.02.018

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

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105 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 language	English (US)
Pages (from-to)	351-361
Number of pages	11
Journal	Molecular cell
Volume	46
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2012.02.018
State	Published - May 11 2012

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2012.02.018

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@article{c7d4d7d3d0d047149ef472982082ea25,

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.",

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

note = "Funding Information: We thank Dr. Keiichi I. Nakayama for Skp2 −/− mice, and Drs. Junjie Chen, Dean Tang, Shiaw-Yih Lin, and Li Ma for cells and reagents. We extend special thanks to Dr. Zheng-Bo Han and Su Zhang for their technical support. This study was supported by MD Anderson Research Scholar Fund, National Institutes of Health (NIH) RO1 grants, a Cancer Prevention Research Institute of Texas (CPRIT) grant, a Department of Defense (DOD) grant to H.-K.L., and China Scholarship Council fund to J. Wu. ",

year = "2012",

month = may,

day = "11",

doi = "10.1016/j.molcel.2012.02.018",

language = "English (US)",

volume = "46",

pages = "351--361",

journal = "Molecular cell",

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T1 - Skp2 E3 Ligase Integrates ATM Activation and Homologous Recombination Repair by Ubiquitinating NBS1

AU - Wu, Juan

AU - Zhang, Xian

AU - Zhang, Ling

AU - Wu, Ching Yuan

AU - Rezaeian, Abdol Hossein

AU - Chan, Chia Hsin

AU - Li, Ju Mei

AU - Wang, Jing

AU - Gao, Yuan

AU - Han, Fei

AU - Jeong, Yun Seong

AU - Yuan, Xiandao

AU - Khanna, Kum Kum

AU - Jin, Jianping

AU - Zeng, Yi Xin

AU - Lin, Hui Kuan

N1 - Funding Information: We thank Dr. Keiichi I. Nakayama for Skp2 −/− mice, and Drs. Junjie Chen, Dean Tang, Shiaw-Yih Lin, and Li Ma for cells and reagents. We extend special thanks to Dr. Zheng-Bo Han and Su Zhang for their technical support. This study was supported by MD Anderson Research Scholar Fund, National Institutes of Health (NIH) RO1 grants, a Cancer Prevention Research Institute of Texas (CPRIT) grant, a Department of Defense (DOD) grant to H.-K.L., and China Scholarship Council fund to J. Wu.

PY - 2012/5/11

Y1 - 2012/5/11

N2 - 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.

AB - 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.

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JO - Molecular cell

JF - Molecular cell

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ER -

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

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