Regulation of Non-homologous end joining by mono-ubiqutination of 53BP1

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We show that RAD18 is recruited at sites of DNA double-strand breaks (DSBs) forming foci which are co-localized with 53BP1. RAD18 associates with 53BP1 and is recruited at DSB sites in a 53BP1-dependent manner specifically during G1-phase. RAD18 mono- ubiquitinates 53BP1 at lysine 1268 in vitro. The mono-ubiquitination resistant 53BP1 mutant harboring a substitution at lysine 1268 is not retained efficiently at the chromatin in the vicinity of DSBs. In Rad18-null cells, retention of 53BP1 foci, efficacy of DSB repair and post-irradiation viability are impaired compared with wild-type cells. Taken together, these results suggest that RAD18 promotes 53BP1- mediated DSB repair by enhancing retention of 53BP1, possibly through an interaction between RAD18 and 53BP1 and the mono-ubiquitination of 53BP1.