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

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...

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Bibliographic Details
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
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Summary: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.
ISSN:0261-4189
1460-2075
DOI:10.1038/emboj.2009.156