Sequence-specific double strand breaks trigger P-TEFb-dependent Rpb1-CTD hyperphosphorylation

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• 作者：Giuliana Napolitano ; Stefano Amente ; Miriam Lubrano Lavadera ; Giacomo Di Palo ; Susanna Ambrosio ; Luigi Lania ; Gaetano Ivan Dellino ; Pier Giuseppe Pelicci ; Barbara Majello
• 关键词：Site-specific DSBs ; AsiSI restriction enzyme ; Rpb1-CTD ; P-TEFb
• 刊名：Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：749
• 期：1-2
• 页码：21-27
• 全文大小：2189 K

文摘

Double strand DNA breaks (DSBs) are one of the most challenging forms of DNA damage which, if left unrepaired, can trigger cellular death and can contribute to cancer. A number of studies have been focused on DNA-damage response (DDR) mechanisms, and most of them rely on the induction of DSBs triggered by chemical compounds or radiations. However, genotoxic drugs and radiation treatments of cultured cell lines induce random DSBs throughout the genome, thus heterogeneously across the cell population, leading to variability of the cellular response. To overcome this aspect, we used here a recently described cell-based DSBs system whereby, upon induction of an inducible restriction enzyme, hundreds of site-specific DSBs are generated across the genome. We show here that sequence-specific DSBs are sufficient to activate the positive transcription elongation factor b (P-TEFb), to trigger hyperphosphorylation of the largest RNA polymerase II carboxyl-terminal-domain (Rpb1-CTD) and to induce activation of p53-transcriptional axis resulting in cell cycle arrest.