1 Department of Molecular Biology and Genetics - Genome stability and technology, Department of Molecular Biology and Genetics, Science and Technology, Aarhus University2 Department of Molecular Biology and Genetics - Danish Centre for Molecular Gerontology, Department of Molecular Biology and Genetics, Science and Technology, Aarhus University3 Danish Centre for Molecular Gerontology, Faculty of Science, Aarhus University, Aarhus University4 Department of Molecular Biology, Faculty of Science, Aarhus University, Aarhus University5 Laboratory of Medical Genetics, University of Strasbourg6 National Institute on Aging, NIH, Baltimore, MD, USA7 University of Strasbourg8 Department of Molecular Biology and Genetics - Genome stability and technology, Department of Molecular Biology and Genetics, Science and Technology, Aarhus University
Cockayne syndrome type B ATPase (CSB) belongs to the SwItch/Sucrose nonfermentable family. Its mutations are linked to Cockayne syndrome phenotypes and classically are thought to be caused by defects in transcription-coupled repair, a subtype of DNA repair. Here we show that after UV-C irradiation, immediate early genes such as activating transcription factor 3 (ATF3) are overexpressed. Although the ATF3 target genes, including dihydrofolate reductase (DHFR), were unable to recover RNA synthesis in CSB-deficient cells, transcription was restored rapidly in normal cells. There the synthesis of DHFR mRNA restarts on the arrival of RNA polymerase II and CSB and the subsequent release of ATF3 from its cAMP response element/ATF target site. In CSB-deficient cells ATF3 remains bound to the promoter, thereby preventing the arrival of polymerase II and the restart of transcription. Silencing of ATF3, as well as stable introduction of wild-type CSB, restores RNA synthesis in UV-irradiated CSB cells, suggesting that, in addition to its role in DNA repair, CSB activity likely is involved in the reversal of inhibitory properties on a gene-promoter region. We present strong experimental data supporting our view that the transcriptional defects observed in UV-irradiated CSB cells are largely the result of a permanent transcriptional repression of a certain set of genes in addition to some defect in DNA repair.
Proceedings of the National Academy of Sciences of the United States of America, 2013, Vol 110, Issue 25, p. 2261-2270