title: MicroRNA-mediated gene silencing modulates the UV-induced DNA-damage response.
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.
authors.affiliation: Department of Cell Biology and Genetics, Erasmus MC, CA Rotterdam 3000, The Netherlands.
authors.forename: Joris
authors.initials: J
authors.lastname: Pothof
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Verkaik
authors.forename: Wilfred
authors.initials: W
authors.lastname: van IJcken
authors.forename: Erik A C
authors.initials: EA
authors.lastname: Wiemer
authors.forename: Van T B
authors.initials: VT
authors.lastname: Ta
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: Nicolaas G J
authors.initials: NG
authors.lastname: Jaspers
authors.forename: Dik C
authors.initials: DC
authors.lastname: van Gent
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Stephan P
authors.initials: SP
authors.lastname: Persengiev
mesh_terms: D060565:Argonaute Proteins; D049109:Cell Proliferation; D002478:Cells, Cultured; D003594:Cytoplasmic Granules; D004260:DNA Repair; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D016193:G1 Phase; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D016196:S Phase; D014466:Ultraviolet Rays
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D015852:Eukaryotic Initiation Factor-2; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D043244:Ribonuclease III