OTUD5 promotes end-joining of deprotected telomeres by promoting ATM-dependent phosphorylation of KAP1^S824

Area of Science:

• Cellular biology
• Molecular genetics
• Biochemistry

Background:

• DNA damage response (DDR) signaling involves complex post-translational modifications, including phosphorylation and ubiquitination.
• The interplay between ubiquitination and phosphorylation in DNA repair at telomeres remains incompletely understood.
• KAP1 phosphorylation at serine 824 (KAP1^S824) is a key marker of DDR at deprotected telomeres.

Purpose of the Study:

• To identify ubiquitin system factors involved in KAP1^S824 phosphorylation at deprotected telomeres.
• To elucidate the molecular mechanisms by which these factors regulate DDR and DNA repair at telomeres and heterochromatin.

Main Methods:

• Functional genetic screen to identify ubiquitin system factors.
• Western blotting to detect KAP1^S824 phosphorylation.
• Assays to measure DNA repair at telomeres and heterochromatin.

Main Results:

• The deubiquitinase OTUD5 was identified as a promoter of KAP1^S824 phosphorylation.
• OTUD5 stabilizes the ubiquitin ligase UBR5, which is crucial for ATM activation and DDR.
• Loss of OTUD5 impairs DNA repair at telomeres and heterochromatin, and KAP1 was found to suppress telomere repair.

Conclusions:

• OTUD5 plays a critical role in relaying DDR signaling to control DNA repair at telomeres and heterochromatin.
• The study reveals a novel mechanism involving OTUD5, UBR5, and ATM in DDR.
• KAP1 has an unexpected function in suppressing DNA repair at telomeres.