Abstract
The WD40 domain-containing protein WRAP53β (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 WRAP53β as an essential regulator of DNA double-strand break (DSB) repair. WRAP53β rapidly localizes to DSBs in an ATM-, H2AX-, and MDC1-dependent manner. We show that WRAP53β 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 WRAP53β facilitates their interaction and accumulation of RNF8 at DSBs. In this manner, WRAP53β controls proper ubiquitylation at DNA damage sites and the downstream assembly of 53BP1, BRCA1, and RAD51. Furthermore, we reveal that knockdown of WRAP53β 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 WRAP53β as a novel regulator of DSB repair by providing a scaffold for DNA repair factors.
Highlights
Proper repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genome stability and prevention of disease; e.g., neurodegeneration, premature aging, and cancer (Jackson and Bartek 2009)
Our findings reveal that WRAP53b targets the critical ubiquitin ligase RNF8 to DNA lesions by promoting MDC1–RNF8 interactions
In agreement with previous reports, we found that localization of RNF8 to DSBs is dependent on its interaction with MDC1
Summary
Proper repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genome stability and prevention of disease; e.g., neurodegeneration, premature aging, and cancer (Jackson and Bartek 2009). GENES & DEVELOPMENT 28:2726–2738 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/14; www.genesdev.org dipeptide), these proteins can interact with several partners simultaneously in a nonexclusive manner, thereby facilitating protein interactions (Stirnimann et al 2010; Xu and Min 2011). One such example is PALB2, which provides a scaffold for interactions between BRCA1, BRCA2, and RAD51, thereby anchoring BRCA2 to sites of DNA damage. Defects in PALB2 lead to impaired formation of this complex and defective homologous recombination (HR) repair, highlighting the critical role played by scaffold proteins in the DDR (Xia et al 2006; Lan et al 2009; Sy et al 2009)
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