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Mol Cell. 2019 Feb 22. pii: S1097-2765(19)30053-X. doi: 10.1016/j.molcel.2019.01.033. [Epub ahead of print]

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

Author information

1
Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki 00014, Finland.
2
Institute for Informatics, Ludwig-Maximilians-Universität München, 80333 Munich, Germany.
3
Institute of Structural Biology, University of Bonn, 53127 Bonn, Germany.
4
Division of Brain Sciences, Department of Medicine, Imperial College London, London W12 0NN, UK; MRC-Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
5
Departments of Medicine, Microbiology, and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
6
Institute for Virology and Immunobiology, University of Würzburg, 97078 Würzburg, Germany.
7
Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, 2200 Copenhagen, Denmark.
8
MRC-Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Institute of Neurology, University College London, London WC1N 3BG, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
9
Department of Biochemistry and Developmental Biology, University of Helsinki, Helsinki 00014, Finland. Electronic address: matjaz.barboric@helsinki.fi.

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.

KEYWORDS:

7SK snRNP; CDK9; DNA damage response; P-TEFb; Pol II elongation; Pol II pause release; RBM7; apoptosis; genotoxic stress; p38 MAP kinase

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