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Research Article

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Renier Vélez-Cruz, Anton S. Zadorin, Frédéric Coin, and Jean-Marc Egly
  1. 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

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PNAS January 15, 2013 110 (3) E212-E220; https://doi.org/10.1073/pnas.1213076110
Renier Vélez-Cruz
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
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Anton S. Zadorin
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
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Frédéric Coin
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
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Jean-Marc Egly
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
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  • For correspondence: egly@igbmc.fr
  1. Edited by Philip C. Hanawalt, Stanford University, Stanford, CA, and approved November 28, 2012 (received for review August 23, 2012)

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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.

  • nucleotide excision repair
  • sirtuins
  • aging
  • progeria

Footnotes

  • ↵1Present address: Department of Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Science Park Research Division, Smithville, TX 78657.

  • ↵2R.V.-C. and A.S.Z. contributed equally to this work.

  • ↵3To whom correspondence should be addressed. E-mail: egly{at}igbmc.fr.
  • Author contributions: R.V.-C. and J.-M.E. designed research; R.V.-C. and A.S.Z. performed research; F.C. contributed new reagents/analytic tools and discussions; R.V.-C., A.S.Z., and J.-M.E. analyzed data; and R.V.-C. and J.-M.E. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • See Author Summary on page 814 (volume 110, number 3).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1213076110/-/DCSupplemental.

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Sirt1 represses transcription after UV in XP-D/CS
Renier Vélez-Cruz, Anton S. Zadorin, Frédéric Coin, Jean-Marc Egly
Proceedings of the National Academy of Sciences Jan 2013, 110 (3) E212-E220; DOI: 10.1073/pnas.1213076110

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Sirt1 represses transcription after UV in XP-D/CS
Renier Vélez-Cruz, Anton S. Zadorin, Frédéric Coin, Jean-Marc Egly
Proceedings of the National Academy of Sciences Jan 2013, 110 (3) E212-E220; DOI: 10.1073/pnas.1213076110
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