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

Author

Listed:
  • Qinglei Hang

    (The University of Texas MD Anderson Cancer Center)

  • Liyong Zeng

    (The University of Texas MD Anderson Cancer Center)

  • Li Wang

    (The University of Texas MD Anderson Cancer Center)

  • Litong Nie

    (The University of Texas MD Anderson Cancer Center)

  • Fan Yao

    (The University of Texas MD Anderson Cancer Center
    Huazhong Agricultural University)

  • Hongqi Teng

    (The University of Texas MD Anderson Cancer Center)

  • Yalan Deng

    (The University of Texas MD Anderson Cancer Center)

  • Shannon Yap

    (The University of Texas MD Anderson Cancer Center)

  • Yutong Sun

    (The University of Texas MD Anderson Cancer Center)

  • Steven J. Frank

    (The University of Texas MD Anderson Cancer Center)

  • Junjie Chen

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences)

  • Li Ma

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences)

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.

Suggested Citation

  • 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, 2021. "Non-canonical function of DGCR8 in DNA double-strand break repair signaling and tumor radioresistance," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24298-z
    DOI: 10.1038/s41467-021-24298-z
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