Regulatory ubiquitylation during the response to DNA double‐strand breaks

Abstract

The chromatin‐based response to DNA double‐strand breaks (DSBs) is characterized by the accumulation of DNA repair factors and DNA damage signaling molecules within a large domain that surrounds the lesion. This response is largely dependent on ATM‐dependent phosphorylation but also on chromatin ubiquitylation. Indeed, the RNF8 and RNF168 E3 ubiquitin ligases are necessary for the accumulation of proteins such as 53BP1, BRCA1 and RAD18 at sites of DNA damage. The critical importance of this pathway is manifested by the observation that biallelic mutations in the RNF168 gene results in an ataxia‐telangiectasia‐like syndrome referred to as RIDDLE. We are interested in understanding how this pathway is regulated and how ubiquitin‐dependent protein interactions orchestrate the hierarchy of protein recruitment at sites of DNA lesions. I will present our current understanding on the regulation and organization of this signaling cascade and in particular, I will focus my presentation on addressing how 53BP1 is recruited at site of DNA damage, in a ubiquitin‐dependent manner.