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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.
Highlights
DNA double-strand break (DSB) signaling and repair are critical for genome integrity
We show that Peli[1] is likely to be an immediate DSB-responsive ubiquitin ligase that is activated by Ataxia telangiectasia mutated (ATM)-mediated phosphorylation, subsequently promoting the accumulation of ATM and MRN complex at DSB sites via NBS1 ubiquitination
To delineate whether Peli[1] might participate in the established DNAdamage signaling cascade, we examined the distribution of GFPPeli[1] in cells depleted of various DNA-damage signaling factors such as H2AX, MDC1, MRE11, and CtIP following microirradiation
Summary
DNA double-strand break (DSB) signaling and repair are critical for genome integrity. Interaction of Peli[1] 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. These results provide a DSB-responsive factor underlying the connection between ATM kinase and DSB-induced ubiquitination. DSBs trigger DNA damage response (DDR), which regulates specialized cellular processes such as cell cycle checkpoint and promotes activation of DNA repair pathways. These interactions are vital for various DDRs. Interaction between NBS1 and phosphorylated histone H2AX is responsible for recruitment of NBS1 to DSB sites[11]. As a part of the MRN complex, NBS1 exhibits a pleiotropic role in DNA repair
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