Disrupted STIL-BRCA1 axis causes centrosome amplification and genomic instability.

Centrosome abnormalities can lead to erroneous chromosome segregation during cell division, resulting in genomic instability. We identified a cancer-associated heterozygous missense mutation (S76L) in the centrosome protein STIL that promotes centrosome amplification and DNA damage. STIL was found to interact with BRCA1 regulating its stability; this, however, is disrupted by the S76L mutation. Mimicking the heterozygous state by overexpressing STIL-S76L redistributed BRCA1 from the nucleus to centrosomes and elevated centrosomal Aurora-A and PLK1 kinases that are responsible for centrosome amplification. Decreased nuclear BRCA1 in the mutant state induced DNA damage, which was rescued by co-expression of wild-type but not nuclear localization-deficient BRCA1. Despite amplified centrosomes, mutant cells maintain pseudo-bipolar spindle organization via kinesin HSET (KIFC1)-dependent clustering, a known cancer survival mechanism and potential therapeutic target. Together, our findings uncover a previously unrecognized STIL-BRCA1 regulatory axis that safeguards centrosome homeostasis and genome integrity. Impact statement Our study reveals a cancer-associated STIL mutation that disrupts its interaction with BRCA1, thereby destabilizing BRCA1 and leading to centrosome amplification and DNA damage.