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

Andrii Bugai, Alexandre Jose Christino Quaresma, Caroline C. Friedel, Valentina 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
ISSN1097-2765
DOIs
Publication statusPublished - 2019
MoE publication typeA1 Journal article-refereed

Cite this

Bugai, Andrii ; Christino Quaresma, Alexandre Jose ; Friedel, Caroline C. ; Lenasi, Valentina ; Düster, Robert ; Sibley, Christopher R. ; Fuginaga, Koh ; Kukanja, Petra ; Hennig, Thomas ; Blasius, Melanie ; Geyer, Matthias ; Ule, Jernej ; Dölken, Lars ; Barboric, Matjaz. / P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress. In: Molecular Cell. 2019.
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title = "P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress.",
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.",
author = "Andrii Bugai and {Christino Quaresma}, {Alexandre Jose} and Friedel, {Caroline C.} and Valentina Lenasi and Robert D{\"u}ster and Sibley, {Christopher R.} and Koh Fuginaga and Petra Kukanja and Thomas Hennig and Melanie Blasius and Matthias Geyer and Jernej Ule and Lars D{\"o}lken and Matjaz Barboric",
year = "2019",
doi = "10.1016/j.molcel.2019.01.033",
language = "English",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",

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Bugai, A, Christino Quaresma, AJ, Friedel, CC, Lenasi, V, Düster, R, Sibley, CR, Fuginaga, K, Kukanja, P, Hennig, T, Blasius, M, Geyer, M, Ule, J, Dölken, L & Barboric, M 2019, 'P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress.', Molecular Cell. https://doi.org/10.1016/j.molcel.2019.01.033

P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress. / Bugai, Andrii; Christino Quaresma, Alexandre Jose; Friedel, Caroline C.; Lenasi, Valentina; Düster, Robert; Sibley, Christopher R.; Fuginaga, Koh; Kukanja, Petra; Hennig, Thomas; Blasius, Melanie; Geyer, Matthias; Ule, Jernej; Dölken, Lars; Barboric, Matjaz.

In: Molecular Cell, 2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress.

AU - Bugai, Andrii

AU - Christino Quaresma, Alexandre Jose

AU - Friedel, Caroline C.

AU - Lenasi, Valentina

AU - Düster, Robert

AU - Sibley, Christopher R.

AU - Fuginaga, Koh

AU - Kukanja, Petra

AU - Hennig, Thomas

AU - Blasius, Melanie

AU - Geyer, Matthias

AU - Ule, Jernej

AU - Dölken, Lars

AU - Barboric, Matjaz

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2019.01.033

DO - 10.1016/j.molcel.2019.01.033

M3 - Article

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

ER -