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MicroRNA‐mediated gene silencing modulates the UV‐induced DNA‐damage response
Author(s) -
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
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.156
Subject(s) - biology , dna damage , gene silencing , microrna , dna , gene , microbiology and biotechnology , rna interference , regulation of gene expression , sos response , genetics , rna
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.