RT Journal Article
SR Electronic
T1 P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 394239
DO 10.1101/394239
A1 Andrii Bugai
A1 Alexandre J.C. Quaresma
A1 Caroline C. Friedel
A1 Tina Lenasi
A1 Christopher R. Sibley
A1 Petra Kukanja
A1 Koh Fujinaga
A1 Melanie Blasius
A1 Thomas Hennig
A1 Jernej Ule
A1 Lars Dölken
A1 Matjaz Barboric
YR 2018
UL http://biorxiv.org/content/early/2018/08/17/394239.abstract
AB Cellular DNA damage response (DDR) involves dramatic transcriptional alterations, the mechanisms of which remain ill-defined. Given the centrality of RNA polymerase II (Pol II) promoter-proximal pause release in transcriptional control, we evaluated its importance in DDR. Here we show that following genotoxic stress, the RNA-binding motif protein 7 (RBM7) stimulates Pol II elongation and promotes cell viability by activating the positive transcription elongation factor b (P-TEFb). This is mediated by genotoxic stress-enhanced binding of RBM7 to 7SK snRNA (7SK), the scaffold of the 7SK small nuclear ribonucleoprotein (7SK snRNP) which inhibits P-TEFb. In turn, P-TEFb relocates from 7SK snRNP to chromatin to induce transcription of short units including key DDR genes and multiple classes of non-coding RNAs. Critically, interfering with RBM7 or P-TEFb provokes cellular hypersensitivity to DNA damage-inducing agents through activation of apoptotic program. By alleviating the inhibition of P-TEFb, RBM7 thus facilitates Pol II elongation to enable a pro-survival transcriptional response that is crucial for cell fate upon genotoxic insult. Our work uncovers a new paradigm in stress-dependent control of Pol II pause release, and offers the promise for designing novel anti-cancer interventions using RBM7 and P-TEFb antagonists in combination with DNA-damaging chemotherapeutics.