MicroRNA‐mediated gene silencing modulates the UV‐induced DNA‐damage response

• Published in: The EMBO journal 2009-07, Vol.28 (14), p.2090-2099
• Main Authors: Pothof, Joris, Verkaik, Nicole S, van IJcken, Wilfred, Wiemer, Erik A C, Ta, Van T B, van der Horst, Gijsbertus T J, Jaspers, Nicolaas G J, van Gent, Dik C, Hoeijmakers, Jan H J, Persengiev, Stephan P
• Format: Article
• Language: English
• Subjects: Apoptosis; Argonaute Proteins; Cell cycle; cell cycle checkpoints; Cell Proliferation; Cells, Cultured; Cytoplasmic Granules; Deoxyribonucleic acid; DNA; DNA damage; DNA Repair; EMBO13; EMBO36; Eukaryotic Initiation Factor-2 - genetics; Eukaryotic Initiation Factor-2 - metabolism; Fibroblasts - cytology; G1 Phase; Gene expression; Gene Silencing; HeLa Cells; Humans; microRNAs; MicroRNAs - genetics; Ribonuclease III - genetics; Ribonuclease III - metabolism; S Phase; stress granules; Ultraviolet Rays
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2009.156

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.