Centriolar subdistal appendages promote double‐strand break repair through homologous recombination

Abstract

The centrosome is a cytoplasmic organelle with roles in microtubule organization that has also been proposed to act as a hub for cellular signaling. Some centrosomal components are required for full activation of the DNA damage response. However, whether the centrosome regulates specific DNA repair pathways is not known. Here, we show that centrosome presence is required to fully activate recombination, specifically to completely license its initial step, the so‐called DNA end resection. 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. Cells lacking centrosomes or depleted for CEP170 are, consequently, hypersensitive 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 that changes in CEP170 can act as a mutation driver but could also be targeted to improve current oncological treatments. image Centriolar subdistal appendages and in particular their component CEP170 promote double‐strand break repair by homologous recombination (HR). Therefore, CEP170 presence modulates sensitivity to DNA damaging agents. Centrioles are required for fully proficient double‐strand break repair by HR. Subdistal appendage proteins promote DNA end resection from the centriole, mostly by the presence of CEP170 at this structure. CEP170 phosphorylation at Ser637 is required for efficient HR‐mediated DNA repair. Centrioles and CEP170 are required for cell survival upon exposure to agents that cause DNA double‐strand breaks.