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miR-34 activity is modulated through 5′-end phosphorylation in response to DNA damage

Author

Listed:
  • David W. Salzman

    (Yale School of Medicine)

  • Kotoka Nakamura

    (David Geffen School of Medicine)

  • Sunitha Nallur

    (Yale School of Medicine)

  • Michelle T. Dookwah

    (Yale School of Medicine)

  • Chanatip Metheetrairut

    (Cellular and Developmental Biology, Yale University)

  • Frank J. Slack

    (Cellular and Developmental Biology, Yale University
    Beth Israel Deaconess Medical Center, Institute for RNA Medicine, Harvard Medical School)

  • Joanne B. Weidhaas

    (David Geffen School of Medicine)

Abstract

MicroRNA (miRNA) expression is tightly regulated by several mechanisms, including transcription and cleavage of the miRNA precursor RNAs, to generate a mature miRNA, which is thought to be directly correlated with activity. MiR-34 is a tumour-suppressor miRNA important in cell survival, that is transcriptionally upregulated by p53 in response to DNA damage. Here, we show for the first time that there is a pool of mature miR-34 in cells that lacks a 5′-phosphate and is inactive. Following exposure to a DNA-damaging stimulus, the inactive pool of miR-34 is rapidly activated through 5′-end phosphorylation in an ATM- and Clp1-dependent manner, enabling loading into Ago2. Importantly, this mechanism of miR-34 activation occurs faster than, and independently of, de novo p53-mediated transcription and processing. Our study reveals a novel mechanism of rapid miRNA activation in response to environmental stimuli occurring at the mature miRNA level.

Suggested Citation

  • David W. Salzman & Kotoka Nakamura & Sunitha Nallur & Michelle T. Dookwah & Chanatip Metheetrairut & Frank J. Slack & Joanne B. Weidhaas, 2016. "miR-34 activity is modulated through 5′-end phosphorylation in response to DNA damage," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10954
    DOI: 10.1038/ncomms10954
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