Histone ubiquitination by the DNA damage response is required for efficient DNA replication in unperturbed S-phase. Schmid et al.
Aiming at better understanding the role of non-canonical ubiquitin-mediated events in the control of DNA replication, we made quite relevant observations on the role of key DNA damage response factors – ATM/RNF8/RNF168/53BP1 – in ensuring complete and accurate DNA replication. In a nutshell, we found that the histone ubiquitin ligase RNF168 associates with PCNA at a subset of replication factories and is required for proper DNA replication in unperturbed S phase. RNF168-deficient cells show accumulation of reversed forks and reduced fork speed, which relies on MRE11-dependent reversed fork processing. These replication phenotypes are shared with other key DDR factors, ATM, RNF8 and 53BP1, and are recapitulated in cells derived from patients affected by the RIDDLE and Ataxia Telangiectasia syndromes, caused by loss of RNF168 and ATM, respectively. RNF168-deficient cells show defects in replicating a prototype of difficult-to-replicate regions, i.e. expanded GAA repeats, previously shown to induce transient fork slowing and remodelling. These replication defects are associated with detectable chromosome abnormalities in mitosis.