Work

OTUD5 promotes end-joining of deprotected telomeres by promoting ATM-dependent phosphorylation of KAP1S824

Year: 2024

Type: article

Abstract: Appropriate repair of damaged DNA and the suppression of DNA damage responses at telomeres are essential to preserve genome stability. DNA damage response (DDR) signaling consists of cascades of kinase-driven phosphorylation events, fine-tuned by proteolytic and regulatory ubiquitination. It is not fully understood how crosstalk between these two major classes of post-translational modifications impact DNA repair at deprotected telomeres. Hence, we performed a functional genetic screen to search for ubiquitin system factors that promote KAP1S824 phosphorylation, a robust DDR marker at deprotected telomeres. We identified that the OTU family deubiquitinase (DUB) OTUD5 promotes KAP1S824 phosphorylation by facilitating ATM activation, through stabilization of the ubiquitin ligase UBR5 that is required for DNA damage-induced ATM activity. Loss of OTUD5 impairs KAP1S824 phosphorylation, which suppresses end-joining mediated DNA repair at deprotected telomeres and at DNA breaks in heterochromatin. Moreover, we identified an unexpected role for the heterochromatin factor KAP1 in suppressing DNA repair at telomeres. Altogether our work reveals an important role for OTUD5 and KAP1 in relaying DDR-dependent kinase signaling to the control of DNA repair at telomeres and heterochromatin. Ubiquitination factors play crucial roles in DNA repair. The authors show that deubiquitinase OTUD5 facilitates ATM-dependent DNA damage signalling via the UBR5-ATMIN axis. OTUD5 loss results in DNA repair defects at heterochromatin and deprotected telomeres due to insufficient KAP1S824 phosphorylation.

Source: Nature Communications

DOI: 10.1038/s41467-024-53404-0