title: Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells.
abstract: Specific mutations in the XPD subunit of transcription factor IIH result in combined xeroderma pigmentosum (XP)/Cockayne syndrome (CS), a severe DNA repair disorder characterized at the cellular level by a transcriptional arrest following UV irradiation. This transcriptional arrest has always been thought to be the result of faulty transcription-coupled repair. In the present study, we showed that, following UV irradiation, XP-D/CS cells displayed a gross transcriptional dysregulation compared with "pure" XP-D cells or WT cells. Furthermore, global RNA-sequencing analysis showed that XP-D/CS cells repressed the majority of genes after UV, whereas pure XP-D cells did not. By using housekeeping genes as a model, we demonstrated that XP-D/CS cells were unable to reassemble these gene promoters and thus to restart transcription after UV irradiation. Furthermore, we found that the repression of these promoters in XP-D/CS cells was not a simple consequence of deficient repair but rather an active heterochromatinization process mediated by the histone deacetylase Sirt1. Indeed, RNA-sequencing analysis showed that inhibition of and/or silencing of Sirt1 changed the chromatin environment at these promoters and restored the transcription of a large portion of the repressed genes in XP-D/CS cells after UV irradiation. Our work demonstrates that a significant part of the transcriptional arrest displayed by XP-D/CS cells arises as a result of an active repression process and not simply as a result of a DNA repair deficiency. This dysregulation of Sirt1 function that results in transcriptional repression may be the cause of various severe clinical features in patients with XP-D/CS that cannot be explained by a DNA repair defect.
authors.affiliation: Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale,  Université de Strasbourg, 67404 Illkirch,  France.
authors.forename: Renier
authors.initials: R
authors.lastname: Vélez-Cruz
authors.forename: Anton S
authors.initials: AS
authors.lastname: Zadorin
authors.forename: Frédéric
authors.initials: F
authors.lastname: Coin
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
mesh_terms: D002478:Cells, Cultured; D003057:Cockayne Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D004260:DNA Repair; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D009154:Mutation; D012313:RNA / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051758:Transcription Factor TFIIH / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000528:radiation effects; D014466:Ultraviolet Rays / Q000009:adverse effects; D014983:Xeroderma Pigmentosum / Q000150:complications / Q000235:genetics* / Q000378:metabolism*; D051759:Xeroderma Pigmentosum Group D Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D006570:Heterochromatin; D012333:RNA, Messenger; D051758:Transcription Factor TFIIH; D012313:RNA; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human