The transcriptional response to distinct growth factors is impaired in Werner syndrome cells.
The Werner syndrome protein (WRN) is mutated in Werner syndrome (WS) and plays a role in telomere maintenance, DNA repair and transcription. WS represents a premature aging syndrome with severe growth retardation. Here we show that WRN is critically required to mediate the stimulatory effect of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-b) and epidermal growth factor (EGF) on the activity of RNA polymerase I (Pol I). Recombinant WRN specifically reconstitutes RNA polymerase I transcription in extracts from Werner syndrome fibroblasts in vitro. In addition, we identified a critical role for WRN during promoter clearance of Pol I transcription, but not in elongation. Notably, WRN was isolated in a complex with Pol I and was crosslinked to the unmethylated, active proportion of rDNA genes in quiescent cells suggesting a so far unknown role for WRN in epigenetic regulation. This together with alterations in Pol I transcription provide a novel mechanism possibly underlying at least in part the severe growth retardation and premature aging in Werner syndrome patients.
Lutomska
Anna
A
Department of Dermatology and Allergic Diseases, University of Ulm, Maienweg 12, 89081 Ulm, Germany.
Lebedev
Anton
A
Scharffetter-Kochanek
Karin
K
Iben
Sebastian
S
D002478:Cells, Cultured; D019175:DNA Methylation; D004275:DNA, Ribosomal / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D009154:Mutation; D011401:Promoter Regions, Genetic; D012318:RNA Polymerase I / Q000235:genetics; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D014898:Werner Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071657:Werner Syndrome Helicase
D004275:DNA, Ribosomal; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D012318:RNA Polymerase I; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase