Centriolar subdistal appendages promote double strand break repair through homologous recombination

Abstract

AbstractThe centrosome is a cytoplasmic organelle with roles in microtubule organization which has also been proposed to act as a hub for cellular signaling. For example, it has been suggested that some centrosomal component are required for full activation of the DNA Damage Response, the cellular signaling network that is activated upon the appearance of chromosome breaks. However, if the centrosome and/or some of its components regulate specific DNA repair pathways is not known. Double strand breaks are mostly repaired by two alternative mechanisms, the homology-independent non-homologous end-joining and the homology-driven homologous recombination. Here, we show that centrosomes presence is required to fully activate recombination, specifically to completely license its initial step, the so-called DNA end resection. Additionally, loss of centrosome upregulates the non-homologous end-joining repair pathway. Furthermore, we identify a centriolar structure, the subdistal appendages, and a specific factor, CEP170, as the critical centrosomal component involved in the regulation of recombination and resection, albeit it does not control end-joining repair. Cells lacking centrosomes or depleted for CEP170 are, consequently, hyper-sensitive to DNA damaging agents. Moreover, low levels of CEP170 in multiple cancer types correlate with an increase of the mutation burden associated with specific mutational signatures and a better prognosis, suggesting this protein can act as a driver mutation but also could be targeted to improve current oncological treatments.