Centriolar Subdistal Appendages Promote Double-strand Break Repair Through Homologous Recombination

Description

The centrosome is a cytoplasmic organelle with roles in microtu-bule organization that has also been proposed to act as a hub forcellular signaling. Some centrosomal components are required forfull activation of the DNA damage response. However, whether thecentrosome regulates specific DNA repair pathways is not known.Here, we show that centrosome presence is required to fully acti-vate recombination, specifically to completely license its initialstep, the so-called DNA end resection. Furthermore, we identify acentriolar structure, the subdistal appendages, and a specific fac-tor, CEP170, as the critical centrosomal component involved in theregulation of recombination and resection. Cells lacking centro-somes or depleted for CEP170are, consequently, hypersensitive toDNA damaging agents. Moreover, low levels of CEP170in multiplecancer types correlate with an increase of the mutation burdenassociated with specific mutational signatures and a better prog-nosis, suggesting that changes in CEP170can act as a mutationdriver but could also be targeted to improve current oncologicaltreatments.

Abstract

Junta de Andalucía US-1255532

Abstract

Consejería de Transformación Económica, Industria, Conocimiento y Universidades P18-RT- 1204

Abstract

Ministerio de Ciencia e Innovación PID2019-104195G

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