Article
- The EMBO Journal (2009) 28, 2090 - 2099
- doi:10.1038/emboj.2009.156
Published online: 18 June 2009
Subject Categories:
MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response
Joris Pothof1,*, Nicole S Verkaik1,*, Wilfred van IJcken2, Erik A C Wiemer3, Van T B Ta4, Gijsbertus T J van der Horst1, Nicolaas G J Jaspers1, Dik C van Gent1, Jan H J Hoeijmakers1 and Stephan P Persengiev1,*
- Department of Cell Biology and Genetics, Erasmus MC, CA Rotterdam, The Netherlands
- Center for Biomics, Erasmus MC, CA Rotterdam, The Netherlands
- Department of Internal Oncology, Erasmus MC, CA Rotterdam, The Netherlands
- Department of Immunology, Erasmus MC, CA Rotterdam, The Netherlands
Correspondence to:
Jan H J Hoeijmakers, Department of Cell Biology and Genetics, Erasmus University, PO Box 1738, CA Rotterdam 3000, The Netherlands. Tel.: +31 10 408 7199; Fax: +31 10 436 0225; E-mail: j.hoeijmakers@erasmusmc.nl
*These authors contributed equally to this work
*Present addresses: Department of Immunohematology and Blood Transfusion, Leiden Univ Med Cntr, the Netherlands and Division of Complex Genetics, UMC Utrecht, The Netherlands.
Received 31 August 2008; Accepted 18 May 2009
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:
- cell cycle checkpoints,
- DNA damage,
- microRNAs,
- stress granules
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