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

David W. Salzman, Kotoka Nakamura, Sunitha Nallur, Michelle T. Dookwah, Chanatip Metheetrairut, Frank J. Slack and Joanne B. Weidhaas ()
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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
Joanne B. Weidhaas: David Geffen School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10954

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