Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30952868.
- Also identified by DOI 10.1038/s41467-019-09641-9 and PMC identifier 6450972.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Ataxia Telangiectasia Mutated Proteins
- Cell Cycle Proteins
- DNA Repair
- Nuclear Proteins
- Ubiquitin-Protein Ligases