WEHI Wednesday Seminar hosted by Professor Vihandha Wickramasinghe

Professor Tony Cesare

Head – Genome Integrity Unit, Children’s Medical Research Institute

Beyond DNA repair: BRCA2-dependent homologous recombination controls the G2 checkpoint, mitotic death and inflammatory cell fate

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session

BRCA2 is frequently mutated in breast, ovarian, prostate and pancreatic cancers. It is an essential component of the homologous recombination (HR) pathway, which repairs DNA double-strand breaks and maintains genome stability. The prevailing model is that HR deficiency promotes cancer by compromising DNA repair, thereby increasing genome instability and accelerating oncogenic evolution. Our recent work reveals that BRCA2-dependent HR has two additional functions beyond genome restoration. First, HR engagement is required for full activation of the G2 checkpoint following DNA damage. Second, the transmission of unresolved HR repair intermediates into mitosis triggers non-immunogenic intrinsic apoptosis, eliminating damaged cells through mitotic death. HR deficiency therefore causes two interconnected defects: it weakens the G2 checkpoint and prevents the efficient elimination of damaged cells during mitosis. Consequently, chromosome breaks are transmitted through mitosis and into subsequent cell cycles, where they activate cytosolic nucleic acid-sensing pathways and provoke sterile inflammation. These findings redefine HR deficiency as a failure not only to repair damaged genomes, but also to arrest and eliminate the cells that carry them. This framework has implications for understanding BRCA-associated tumour development, therapeutic resistance, synthetic lethality and anti-tumour immunity.

Tony Cesare is Head of the CMRI Genome Integrity Unit, Professor in the University of Sydney Faculty of Medicine and Health, and an NHMRC Leadership Level 2 Investigator. His laboratory investigates fundamental mechanisms of genome protection, including telomere biology, DNA double-strand break repair, and the roles of nuclear forces and chromatin architecture in DNA replication. The lab is particularly interested in how these protective mechanisms determine cell fate when genome integrity is challenged.

All welcome!