The scaffold protein WRAP53? orchestrates the ubiquitin response critical for DNA double-strand break repair.

ABSTRACT: The WD40 domain-containing protein WRAP53? (WD40 encoding RNA antisense to p53; also referred to as WDR79/TCAB1) controls trafficking of splicing factors and the telomerase enzyme to Cajal bodies, and its functional loss has been linked to carcinogenesis, premature aging, and neurodegeneration. Here, we identify WRAP53? as an essential regulator of DNA double-strand break (DSB) repair. WRAP53? rapidly localizes to DSBs in an ATM-, H2AX-, and MDC1-dependent manner. We show that WRAP53? targets the E3 ligase RNF8 to DNA lesions by facilitating the interaction between RNF8 and its upstream partner, MDC1, in response to DNA damage. Simultaneous binding of MDC1 and RNF8 to the highly conserved WD40 scaffold domain of WRAP53? facilitates their interaction and accumulation of RNF8 at DSBs. In this manner, WRAP53? controls proper ubiquitylation at DNA damage sites and the downstream assembly of 53BP1, BRCA1, and RAD51. Furthermore, we reveal that knockdown of WRAP53? impairs DSB repair by both homologous recombination (HR) and nonhomologous end-joining (NHEJ), causes accumulation of spontaneous DNA breaks, and delays recovery from radiation-induced cell cycle arrest. Our findings establish WRAP53? as a novel regulator of DSB repair by providing a scaffold for DNA repair factors.

SUBMITTER: Henriksson S 

PROVIDER: S-EPMC4265676 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature