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

Abstract

Summary 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 p38 MAPK , 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.

Continuous transcription initiation guarantees robust repair of all transcribed genes and regulatory regions

“…In this study, we provide quantitative insights into the molecular processes underlying the major transcription-coordinated cellular response that is activated in human cells upon genotoxic stress [25][26][27]34,35,37 . The establishment of precise maps of chromatin state helped us to query in detail the impact of transcription on DNA repair activities at important functional regions, including PROMPT and eRNA loci.…”

“…3). Interestingly, a growing number of studies have reported data to suggest that (i) UV irradiation preferentially inhibits elongation, rather than transcription initiation [25][26][27]34 , (ii) P-TEFb and NELF are important regulators of UV response 35,37,61 , and (iii) although elongation gradually decelerates due to the encounter of Pol II with DNA lesions, significant initiation/early elongation activity is observed in the first thousand bases of actively transcribed regions 25,26,34 , a characteristic that has also been used for the identification of active TSSs genome-wide after UV 27 . These features are consistent with our finding that new Pol II molecules are constantly recruited to PICs post-UV (see Fig.…”

“…Moreover, depletion of the pre-initiating hypophosphorylated Pol II(hypo) isoform from chromatin shortly after UV irradiation 25,29,30 has led to the assumption that new transcription initiation events are transiently and globally repressed 21,[29][30][31][32][33] . On the other hand, recent reports 25,26,34 have revealed a functionally essential stress-dependent increase in 5′ nascent RNA (nRNA) activity globally that depends on the UVinduced increase in active P-TEFb levels 35,36 , and on the rapid dissociation of the NELF complex 37 . The ensuing fast and global release of de novo Pol II elongation waves from PPP sites into gene bodies boosts lesion-sensing activity and accelerates removal of DNA adducts by TC-NER in virtually all active mRNA genes 25 .…”

Diversity and versatility of p38 kinase signalling in health and disease

“…The p38α pathway can also facilitate the survival of stressed cells through the MK2-mediated phosphorylation of NELFE 105 or RBM7 (ref. 106 ), which enables a RNA polymerase II transcriptional response including genes required for telomere maintenance or DNA repair.…”

P-TEFb as A Promising Therapeutic Target

“…For instance, disrupting 7SK snRNP in cardiomyocytes results in upregulation of global gene expression, leading to cardiac hypertrophy [44]. Many stresses such as UV light, heat, inhibition of transcription, and specific intracellular signaling cascades release P-TEFb from the 7SK snRNP [15,20,126,127]. Also, small compounds such as histone deacetylase inhibitors (HDACis), which include tricostatin A and suberoylanilide hydroxamic acid (SAHA); PKC agonists; bromodomain and extra-terminal (BET) bromodomain inhibitors (BETis); DNA damage-inducing agents; a strong cell-differentiation inducer, hexamethylene bisacetamide (HMBA); and others also release P-TEFb from 7SK snRNP via various known and unknown mechanisms and activate transcription elongation mediated by P-TEFb [14,15,60,[128][129][130][131][132] (Figure 2).…”