Extra centrosomes delay DNA damage-driven tumorigenesis

Centrosomes act as microtubule organizing centers and are critical for faithful chromosome segregation in mitosis. Deregulated centrosome numbers are frequently found in human cancer and can promote malignancies in model organisms. Current research aims to clarify if extra centrosomes are cause or consequence of malignant transformation, and if their biogenesis can be targeted for therapy. Here, we show that oncogene-driven blood cancer is inert to genetic manipulation of centrosome numbers, whereas the formation of DNA damage-induced malignancies is delayed. This unexpected phenomenon is due to extra centrosomes eliciting a pro death signal engaging the apoptotic machinery. Cell death initiation requires the PIDDosome multiprotein complex, as it can be abrogated by loss of any of its three components, Caspase-2, Raidd/Cradd or Pidd1. BCL2 overexpression equally blocks cell death documenting for the first time induction of mitochondrial apoptosis downstream of extra centrosomes. Our findings demonstrate context-dependent effects of centrosome amplification during transformation and ask to adjust current believe that extra centrosomes are intrinsically pro-tumorigenic.