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Mol Cell. 2017 Dec 21;68(6):1054-1066.e6. doi: 10.1016/j.molcel.2017.11.009. Epub 2017 Dec 7.

Cockayne's Syndrome A and B Proteins Regulate Transcription Arrest after Genotoxic Stress by Promoting ATF3 Degradation.

Author information

1
IGBMC, Department of Functional Genomics and Cancer, Equipe Labellisée Ligue 2014, CNRS/INSERM/University of Strasbourg, BP 163, 67404 Illkirch Cedex, C.U. Strasbourg, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France.
2
Unit of Molecular Genetics of Aging, Department of Ecology and Biology, University of Tuscia, 01100 Viterbo, Italy.
3
Laboratory of Medical Genetics, University of Strasbourg, 11 rue Humann, 67000 Strasbourg, France; Department of Pediatric Neurology, Strasbourg University Hospital, Avenue Moliere, 67098 Strasbourg Cedex, France.
4
IGBMC, Department of Functional Genomics and Cancer, Equipe Labellisée Ligue 2014, CNRS/INSERM/University of Strasbourg, BP 163, 67404 Illkirch Cedex, C.U. Strasbourg, France; Centre National de la Recherche Scientifique, UMR7104, 67404 Illkirch, France; Institut National de la Santé et de la Recherche Médicale, U964, 67404 Illkirch, France; Université de Strasbourg, 67404 Illkirch, France. Electronic address: egly@igbmc.fr.

Abstract

Cockayne syndrome (CS) is caused by mutations in CSA and CSB. The CSA and CSB proteins have been linked to both promoting transcription-coupled repair and restoring transcription following DNA damage. We show that UV stress arrests transcription of approximately 70% of genes in CSA- or CSB-deficient cells due to the constitutive presence of ATF3 at CRE/ATF sites. We found that CSB, CSA/DDB1/CUL4A, and MDM2 were essential for ATF3 ubiquitination and degradation by the proteasome. ATF3 removal was concomitant with the recruitment of RNA polymerase II and the restart of transcription. Preventing ATF3 ubiquitination by mutating target lysines prevented recovery of transcription and increased cell death following UV treatment. Our data suggest that the coordinate action of CSA and CSB, as part of the ubiquitin/proteasome machinery, regulates the recruitment timing of DNA-binding factors and provide explanations about the mechanism of transcription arrest following genotoxic stress.

KEYWORDS:

ATF3; CSA; CSB; DNA repair; MDM2; TCR; proteasome; transcription; transcription arrest; ubiquitination

PMID:
29225035
DOI:
10.1016/j.molcel.2017.11.009
[Indexed for MEDLINE]
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