P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress

Bugai, A.; Quaresma, A. J.; Friedel, C. C.; Lenasi, V.; Sibley, C. R.; Kukanja, P.; Fujinaga, K.; Blasius, M.; Hennig, T.; Ule, J.; Doelken, L.; Barboric, M.

doi:10.1101/394239

bioRxiv · 10.1101/394239

P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress

Bugai, A.·Quaresma, A. J.·Friedel, C. C.·Lenasi, V.·Sibley, C. R.·Kukanja, P.·Fujinaga, K.·Blasius, M.·Hennig, T.·Ule, J.·Doelken, L.·Barboric, M.

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Abstract

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.

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Bugai, A., Quaresma, A. J., Friedel, C. C., Lenasi, V., Sibley, C. R., Kukanja, P., Fujinaga, K., Blasius, M., Hennig, T., Ule, J., Doelken, L., Barboric, M.. 2018-08-17. P-TEFb activation by RBM7 shapes a pro-survival transcriptional response to genotoxic stress. https://doi.org/10.1101/394239

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