Oncogenic STIL-mediated loss of BRCA1 functionality causes DNA damage and centrosome amplification

Abstract

DNA damages increase centrosome number, a typical phenotype in many cancers. However, the molecular linkers between the two pathways remain elusive. STIL (SCL/TAL1 Interrupting locus) is a core centrosome-organizing protein overexpressed in different cancer types. This work shows that STIL forms a complex with the DNA damage response protein, BRCA1, and is required for regulating its protein stability. Subsequently, STIL depletion resulting in BRCA1 loss from the nucleus causes centrosome amplification and DNA damage. We also identified a heterozygous missense mutation (S76L) in STIL from the pan-cancer datasets, which does not affect total BRCA1 protein levels. However, it reduces BRCA1 nuclear localization with enhanced centrosome recruitment simultaneously at the S-phase. The enhanced BRCA1 at centrosome causes an increase in Aurora-A kinase levels at centrosomes, thus culminating in DNA damage and centrosome amplification. The expression of exogenous BRCA1 can push back this imbalance of the STIL-BRCA1 axis in oncogenic conditions. The amplified centrosomes in oncogenic STIL condition cluster in the M phase and cause pseudo-bipolar spindle organization. We could decluster them by the HSET(KIFC1)-specific inhibitor, CW069, suggesting a promising target for anti-cancer treatment.