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

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