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

Centrosomes are major microtubule organizing centers in many animal cells and could also act as a communicator between nuclear-cytoplasmic signaling during DNA damages. Therefore, DNA damages cause an increase in centrosome number, however the molecular linkers remain elusive. STIL (SCL/TAL1 Interrupting locus) is a core centrosome organizing protein, which is overexpressed in different cancer types. In this work, we identify a frequently reported heterozygous missense mutation in STIL, which maps to its N-terminal located CR1 region (S76L). The oncogenic STIL-S76L loses interaction with the DNA damage response protein BRCA1 and exhibits a decrease in BRCA1 nuclear localization, which causes DNA damage and enhanced centrosome number. Interestingly, exogenous BRCA1 can rescue these phenotypes of STIL-S76L, thus, establishing it as an effector for the oncogenic STIL functions. These amplified centrosomes tend to cluster in the M phase and cause pseudo bipolar spindle organization, which is a promising target for anti-cancer drugs.