P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress
P-TEFb Activation by RBM7 Shapes a Pro-survival Transcriptional Response to Genotoxic Stress
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DOI：
10.1016/j.molcel.2019.01.033
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发表时间：
2019-04-18
期刊：
影响因子：
16
通讯作者：
Barboric, Matjaz
中科院分区：
文献类型：
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作者：
Bugai, Andrii;Quaresma, Alexandre J. C.;Barboric, Matjaz
DNA损伤反应（DDR）涉及到显著的转录改变，其机制尚不清楚。在这里，我们表明，遗传毒性应激后，RNA结合基序蛋白7（RBM 7）刺激RNA聚合酶II（Pol II）的转录，并通过激活正转录延伸因子B（P-TEF B），通过其从抑制性7 SK小核核糖核蛋白（7 SK snRNP）释放，促进细胞活力。这是由p38（MAPK）的激活介导的，其触发RBM 7与7SK snRNP的核心亚基的结合增强。反过来，P-TEFb重新定位到染色质以诱导短单位的转录，包括关键的DDR基因和多种类别的非编码RNA。重要的是，干扰RBM 7和P-TEFb的轴引起细胞对DNA损伤诱导剂的超敏反应，这是由于细胞凋亡的激活。我们的工作揭示了Pol II暂停释放的应激依赖性刺激的重要性，这使得在遗传毒性损伤后对细胞命运至关重要的促生存转录反应成为可能。
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.