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P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress

Author:
Bugai, Andrii, Quaresma, Alexandre J.C., Friedel, Caroline C., Lenasi, Tina, Düster, Robert, Sibley, Christopher R., Fujinaga, Koh, Kukanja, Petra, Hennig, Thomas, Blasius, Melanie, Geyer, Matthias, Ule, Jernej, Dölken, Lars, Barborič, Matjaž
Source:
Molecular cell 2019 v.74 no.2 pp. 254-267.e10
ISSN:
1097-2765
Subject:
DNA damage, DNA-directed RNA polymerase, apoptosis, cell viability, chromatin, genes, mutagens, non-coding RNA, ribonucleoproteins, transcription (genetics), transcriptional elongation factors
Abstract:
DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill defined. Here, we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates RNA polymerase II (Pol II) transcription and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb) via its release from the inhibitory 7SK small nuclear ribonucleoprotein (7SK snRNP). This is mediated by activation of p38MAPK, which triggers enhanced binding of RBM7 with core subunits of 7SK snRNP. In turn, P-TEFb relocates to chromatin to induce transcription of short units, including key DDR genes and multiple classes of non-coding RNAs. Critically, interfering with the axis of RBM7 and P-TEFb provokes cellular hypersensitivity to DNA-damage-inducing agents due to activation of apoptosis. Our work uncovers the importance of stress-dependent stimulation of Pol II pause release, which enables a pro-survival transcriptional response that is crucial for cell fate upon genotoxic insult.
Agid:
6348371