Non-canonical Function of DGCR8 in DNA Double-strand Break Repair Signaling and Tumor Radioresistance

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Jun 30

PMID 34188037

Citations 14

Authors

Qinglei Hang

Liyong Zeng

Li Wang

Litong Nie

Fan Yao

Hongqi Teng

Yalan Deng

Shannon Yap

Yutong Sun

Steven J Frank

Junjie Chen

Li Ma

Affiliations

Soon will be listed here.

Abstract

In response to DNA double-strand breaks (DSBs), repair proteins are recruited to the damaged sites. Ubiquitin signaling plays a critical role in coordinating protein recruitment during the DNA damage response. Here, we find that the microRNA biogenesis factor DGCR8 promotes tumor resistance to X-ray radiation independently of its Drosha-binding ability. Upon radiation, the kinase ATM and the deubiquitinase USP51 mediate the activation and stabilization of DGCR8 through phosphorylation and deubiquitination. Specifically, radiation-induced ATM-dependent phosphorylation of DGCR8 at serine 677 facilitates USP51 to bind, deubiquitinate, and stabilize DGCR8, which leads to the recruitment of DGCR8 and DGCR8's binding partner RNF168 to MDC1 and RNF8 at DSBs. 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 ATM- and USP51-mediated activation and upregulation of DGCR8.

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