Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks
- Nat Commun. 2019 Apr 5;10(1):1577. doi: 10.1038/s41467-019-09641-9.
- 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. [email protected].
- 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. [email protected].
- 10. Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon, 16499, Republic of Korea. [email protected].
- 11. Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea. [email protected].
- 12. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351, Republic of Korea. [email protected].
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.