TY - JOUR

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

AU - Bugai, Andrii

AU - Quaresma, Alexandre J.C.

AU - Friedel, Caroline C.

AU - Lenasi, Tina

AU - Düster, Robert

AU - Sibley, Christopher R.

AU - Fujinaga, Koh

AU - Kukanja, Petra

AU - Hennig, Thomas

AU - Blasius, Melanie

AU - Geyer, Matthias

AU - Ule, Jernej

AU - Dölken, Lars

AU - Barborič, Matjaž

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.

KW - 7SK snRNP

KW - apoptosis

KW - CDK9

KW - DNA damage response

KW - genotoxic stress

KW - P-TEFb

KW - p38 MAP kinase

KW - Pol II elongation

KW - Pol II pause release

KW - RBM7

U2 - 10.1016/j.molcel.2019.01.033

DO - 10.1016/j.molcel.2019.01.033

M3 - Journal article

C2 - 30824372

AN - SCOPUS:85064186193

VL - 74

SP - 254-267.e10

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 2

ER -