P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress

Andrii Bugai, Alexandre J C Quaresma, Caroline C Friedel, Tina Lenasi, Robert Düster, Christopher R Sibley, Koh Fujinaga, Petra Kukanja, Thomas Hennig, Melanie Blasius, Matthias Geyer, Jernej Ule, Lars Dölken, Matjaž Barborič

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)254-267.e10
Number of pages13
JournalMolecular Cell
Issue number2
Early online date26 Feb 2019
Publication statusPublished - 18 Apr 2019


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