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.
Unit of Molecular Genetics of Aging, Department of Ecology and Biology, University of Tuscia, 01100 Viterbo, Italy.
Mol Cell. 2017 Dec 21;68(6):1054-1066.e6. doi: 10.1016/j.molcel.2017.11.009. Epub 2017 Dec 7.
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.
Cockayne 综合征（CS）是由 CSA 和 CSB 的突变引起的。CSA 和 CSB 蛋白与促进转录偶联修复以及在 DNA 损伤后恢复转录有关。我们表明，由于 ATF3 在 CRE/ATF 位点的组成性存在，UV 应激会导致 CSA 或 CSB 缺陷细胞中约 70%的基因转录停滞。我们发现 CSB、CSA/DDB1/CUL4A 和 MDM2 对于 ATF3 的泛素化和蛋白酶体降解是必需的。ATF3 的去除伴随着 RNA 聚合酶 II 的募集和转录的重新开始。通过突变靶赖氨酸来阻止 ATF3 的泛素化会阻止转录的恢复，并增加 UV 处理后细胞死亡。我们的数据表明，CSA 和 CSB 作为泛素/蛋白酶体机制的一部分的协调作用调节了 DNA 结合因子的募集时机，并提供了关于遗传毒性应激后转录停滞机制的解释。
