TY - JOUR
T1 - Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance
AU - Hang, Qinglei
AU - Zeng, Liyong
AU - Wang, Li
AU - Nie, Litong
AU - Yao, Fan
AU - Teng, Hongqi
AU - Deng, Yalan
AU - Yap, Shannon
AU - Sun, Yutong
AU - Frank, Steven J.
AU - Chen, Junjie
AU - Ma, Li
N1 - Funding Information:
We thank Dr Xiang Zhang (Baylor College of Medicine) for providing the LM2 cell line, Dr Sharon Dent (MD Anderson Cancer Center) for providing the anti-USP51 antibody, Dr Masayuki Komada (Tokyo Institute of Technology) for sharing the anti-USP36 antisera, and Drs Chao Wang, Mengfan Tang, Xu Feng, Jibo Wu, and Dadi Jiang (MD Anderson Cancer Center) for providing reagents and technical assistance. We thank MD Anderson’s Functional Genomics Core and Characterized Cell Line Core Facility for technical support, and Christine Wogan for the critical reading of the manuscript. L.M. is supported by US National Institutes of Health (NIH) grants R01CA166051 and R01CA181029 and a Cancer Prevention and Research Institute of Texas grant RP190029. This work was also supported by an AACR Stand Up To Cancer Innovative Research Grant (award number: 403235) to L.M. and an NIH Cancer Center Support (Core) Grant P30CA016672 to The University of Texas MD Anderson Cancer Center.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41467-021-24298-z
DO - 10.1038/s41467-021-24298-z
M3 - Article
C2 - 34188037
AN - SCOPUS:85108970755
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4033
ER -