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.

Roles for CEP170 in cilia function and dynein-2 assembly

“…CEP170 was originally identified as a binding partner of polo-like kinase 1 (PLK1) in a yeast two-hybrid screen and shown to localise to sDAPs on mother centrioles ( Guarguaglini et al, 2005 ). From this initial work, it was clear that CEP170 has a role in microtubule organisation, and subsequent studies have also linked it with mitosis and DNA damage responses ( Qin et al, 2019 ; Rodriguez-Real et al, 2023 ; Welburn and Cheeseman, 2012 ; Zhang et al, 2019 ). CEP170 has also been shown to interact with the TZ protein RPGRIP1L ( Gupta et al, 2015 ).…”