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Open Access Publications from the University of California

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

  • Author(s): Salzman, David W
  • Nakamura, Kotoka
  • Nallur, Sunitha
  • Dookwah, Michelle T
  • Metheetrairut, Chanatip
  • Slack, Frank J
  • Weidhaas, Joanne B
  • et al.

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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.

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