BAP1 loss impairs Non-Homologous End Joining DNA repair promoting genomic instability

Abstract

The tumor suppressor BRCA1-associated protein 1 (BAP1) is frequently mutated in uveal melanoma, where its loss is associated with poor prognosis. Although BAP1 has been implicated in homologous recombination (HR), its role in non-homologous end-joining (NHEJ) remains poorly defined. Here, we show that BAP1 functions as a central regulator of DNA double-strand break (DSB) repair by coordinating HR and NHEJ. BAP1 depletion disrupts recruitment and activity of the NHEJ machinery. Mechanistically, this defect is driven by aberrant accumulation of H2AK119-ub at DSB sites, promoting excessive DNA end resection and suppressing NHEJ activation. Importantly, inhibition of DNA end resection or suppression of H2AK119-ub restores NHEJ factor recruitment, establishing a causal link between BAP1-regulated histone modifications and repair pathway choice. Clinically, BAP1 loss correlates with genomic instability, providing a mechanistic basis for its association with poor outcomes in uveal melanoma. Collectively, these findings identify BAP1 as a gatekeeper of DSB repair fidelity, revealing a previously unrecognized role in safeguarding NHEJ and maintaining balanced DNA repair.