Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance

Abstract Cells respond to cytotoxic DNA double-strand breaks (DSBs) by recruiting repair proteins to the damaged sites. During the DNA damage response, ubiquitin signaling plays a critical role in coordinating protein recruitment. Here, we find that the microRNA biogenesis factor DGCR8 promotes tumor resistance to X-ray radiation independently of its Drosha-binding ability. In response to radiation, the deubiquitinase USP51 and the kinase ATM mediate the stabilization and activation of DGCR8 through deubiquitination and phosphorylation, respectively. While radiation-induced USP51 binds, deubiquitinates, and stabilizes DGCR8, ATM-dependent phosphorylation of DGCR8 at serine 677 leads to the recruitment of DGCR8 and DGCR8’s binding partner RNF168 to MDC1 and RNF8. This, in turn, promotes ubiquitination of histone H2A, repair of DSBs, and radioresistance. Altogether, these findings reveal the non-canonical function of DGCR8 in DSB repair and suggest that radiation treatment may result in therapy-induced tumor radioresistance through USP51- and ATM-mediated upregulation and activation of DGCR8.