Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks

Geun-Hyoung Ha, Jae-Hoon Ji (), Sunyoung Chae, Jihyun Park, Suhyeon Kim, Jin-Kwan Lee, Yonghyeon Kim, Sunwoo Min, Jeong-Min Park, Tae-Hong Kang, Ho Lee, Hyeseong Cho () and Chang-Woo Lee ()
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Geun-Hyoung Ha: Sungkyunkwan University School of Medicine
Jae-Hoon Ji: Ajou University School of Medicine
Sunyoung Chae: Ajou University School of Medicine
Jihyun Park: Sungkyunkwan University
Suhyeon Kim: Sungkyunkwan University School of Medicine
Jin-Kwan Lee: Sungkyunkwan University
Yonghyeon Kim: Ajou University School of Medicine
Sunwoo Min: Ajou University School of Medicine
Jeong-Min Park: Dong-A University
Tae-Hong Kang: Dong-A University
Ho Lee: Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center
Hyeseong Cho: Ajou University School of Medicine
Chang-Woo Lee: Sungkyunkwan University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract DNA double-strand break (DSB) signaling and repair are critical for genome integrity. They rely on highly coordinated processes including posttranslational modifications of proteins. Here we show that Pellino1 (Peli1) is a DSB-responsive ubiquitin ligase required for the accumulation of DNA damage response proteins and efficient homologous recombination (HR) repair. Peli1 is activated by ATM-mediated phosphorylation. It is recruited to DSB sites in ATM- and γH2AX-dependent manners. Interaction of Peli1 with phosphorylated histone H2AX enables it to bind to and mediate the formation of K63-linked ubiquitination of NBS1, which subsequently results in feedback activation of ATM and promotes HR repair. Collectively, these results provide a DSB-responsive factor underlying the connection between ATM kinase and DSB-induced ubiquitination.

Date: 2019
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DOI: 10.1038/s41467-019-09641-9

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