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 Fuginaga, Petra Kukanja, Thomas Hennig, Melanie Blasius, Matthias Geyer, Jernej Ule, Lars Dölken, Matjaz Barboric

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
JournalMolecular Cell
Volume74
Issue number2
Pages (from-to)254-+
Number of pages24
ISSN1097-2765
DOIs
Publication statusPublished - 18 Apr 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 7SK SNRNP
  • DNA-DAMAGE
  • ELONGATION
  • EXOSOME TARGETING COMPLEX
  • GENE-EXPRESSION
  • INHIBITION
  • NONCODING RNA
  • REPAIR
  • RNA-POLYMERASE-II
  • ULTRAVIOLET-LIGHT
  • 3111 Biomedicine
  • 1182 Biochemistry, cell and molecular biology

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