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Nat Commun. 2019 Apr 5;10(1):1577. doi: 10.1038/s41467-019-09641-9.

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

Author information

1
Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
2
Genomic Instability Research Center, Ajou University School of Medicine, Suwon, 16499, Republic of Korea. jij@ajou.ac.kr.
3
Institute of Medical Science, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
4
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Republic of Korea.
5
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
6
Genomic Instability Research Center, Ajou University School of Medicine, Suwon, 16499, Republic of Korea.
7
Department of Biological Science, Dong-A University, Pusan, 49201, Republic of Korea.
8
Graduate School of Cancer Science and Policy, Research Institute, National Cancer Center, Goyang, 10408, Republic of Korea.
9
Genomic Instability Research Center, Ajou University School of Medicine, Suwon, 16499, Republic of Korea. hscho@ajou.ac.kr.
10
Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 16499, Republic of Korea. hscho@ajou.ac.kr.
11
Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea. cwlee1234@skku.edu.
12
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Republic of Korea. cwlee1234@skku.edu.

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.

PMID:
30952868
PMCID:
PMC6450972
DOI:
10.1038/s41467-019-09641-9
[Indexed for MEDLINE]
Free PMC Article

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