MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response
- 18 June 2009
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 28 (14), 2090-2099
- https://doi.org/10.1038/emboj.2009.156
Abstract
DNA damage provokes DNA repair, cell‐cycle regulation and apoptosis. This DNA‐damage response encompasses gene‐expression regulation at the transcriptional and post‐translational levels. We show that cellular responses to UV‐induced DNA damage are also regulated at the post‐transcriptional level by microRNAs. Survival and checkpoint response after UV damage was severely reduced on microRNA‐mediated gene‐silencing inhibition by knocking down essential components of the microRNA‐processing pathway (Dicer and Ago2). UV damage triggered a cell‐cycle‐dependent relocalization of Ago2 into stress granules and various microRNA‐expression changes. Ago2 relocalization required CDK activity, but was independent of ATM/ATR checkpoint signalling, whereas UV‐responsive microRNA expression was only partially ATM/ATR independent. Both microRNA‐expression changes and stress‐granule formation were most pronounced within the first hours after genotoxic stress, suggesting that microRNA‐mediated gene regulation operates earlier than most transcriptional responses. The functionality of the microRNA response is illustrated by the UV‐inducible miR‐16 that downregulates checkpoint‐gene CDC25a and regulates cell proliferation. We conclude that microRNA‐mediated gene regulation adds a new dimension to the DNA‐damage response.Keywords
This publication has 45 references indexed in Scilit:
- Regulation of the p27Kip1 tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferationThe EMBO Journal, 2007
- MicroRNA Targeting Specificity in Mammals: Determinants beyond Seed PairingMolecular Cell, 2007
- A microRNA component of the p53 tumour suppressor networkNature, 2007
- Transactivation of miR-34a by p53 Broadly Influences Gene Expression and Promotes ApoptosisMolecular Cell, 2007
- Identification of hundreds of conserved and nonconserved human microRNAsNature Genetics, 2005
- MicroRNA expression profiles classify human cancersNature, 2005
- Combinatorial microRNA target predictionsNature Genetics, 2005
- Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA TargetsCell, 2005
- Cancer genes and the pathways they controlNature Medicine, 2004
- Prediction of Mammalian MicroRNA TargetsCell, 2003