biostudies-literatureSalzman DWNIA NIH HHSNCI NIH HHS10954https://www.ebi.ac.uk/biostudies/studies/S-EPMC4802117biostudies-literatureUnknown7MicroRNA (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.Nature communicationsmiR-34 activity is modulated through 5'-end phosphorylation in response to DNA damage.PMC4802117R01 AG033921CA157749P30 CA016042CA131301AG033921R01 CA131301R01 CA157749Dookwah MTNakamura KWeidhaas JBSlack FJSalzman DWMetheetrairut CNallur SfalsemiR-34 activity is modulated through 5'-end phosphorylation in response to DNA damage.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.2016-01-01T00:00:00Z2016 Mar2024-11-14T04:23:28.739Z2019-03-27T03:10:00ZS-EPMC48021172699682410.1038/ncomms10954