Germline mutations in BAP1 impair its function in DNA double-strand break repair

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• The BRCA1-associated deubiquitylase BAP1 is frequently mutated in cancers like mesothelioma and melanoma.
• BAP1's role in oncogenesis is suspected, but its precise function in DNA repair pathways remains unclear.

Purpose of the Study:

• To investigate the function of BAP1 in the DNA damage response (DDR).
• To elucidate the molecular mechanisms underlying BAP1's tumor-suppressive activity.

Main Methods:

• Investigated BAP1's role in DNA double-strand break (DSB) repair.
• Utilized poly(ADP-ribose) (PAR) dependent recruitment assays.
• Identified BAP1 as a phosphorylation target of ATM kinase.

Main Results:

• BAP1 mediates the rapid, PAR-dependent recruitment of the PR-DUB complex to DNA damage sites.
• ATM kinase phosphorylates BAP1, suggesting its integration into DDR signaling.
• BAP1 promotes efficient repair of DNA double-strand breaks, enhancing cell survival.

Conclusions:

• BAP1 is a key component of the DNA damage response, regulating ubiquitin turnover at damage sites.
• BAP1's function in DNA repair and cell survival explains its tumor-suppressive role.
• Understanding BAP1's DDR function offers insights into mesothelioma and melanoma development.