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首页> 外文期刊>Molecular and Cellular Biology >PPM1G Binds 7SK RNA and Hexim1 To Block P-TEFb Assembly into the 7SK snRNP and Sustain Transcription Elongation
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PPM1G Binds 7SK RNA and Hexim1 To Block P-TEFb Assembly into the 7SK snRNP and Sustain Transcription Elongation

机译：PPM1G绑定7SK RNA和Hexim1以阻止P-TEFb组装到7SK snRNP中并维持转录延伸

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Transcription elongation programs are vital for the precise regulation of several biological processes. One key regulator of such programs is the P-TEFb kinase, which phosphorylates RNA polymerase II (Pol II) once released from the inhibitory 7SK small nuclear ribonucleoprotein (snRNP) complex. Although mechanisms of P-TEFb release from the snRNP are becoming clearer, how P-TEFb remains in the 7SK-unbound state to sustain transcription elongation programs remains unknown. Here we report that the PPM1G phosphatase (inducibly recruited by nuclear factor κB [NF-κB] to target promoters) directly binds 7SK RNA and the kinase inhibitor Hexim1 once P-TEFb has been released from the 7SK snRNP. This dual binding activity of PPM1G blocks P-TEFb reassembly onto the snRNP to sustain NF-κB-mediated Pol II transcription in response to DNA damage. Notably, the PPM1G-7SK RNA interaction is direct, kinetically follows the recruitment of PPM1G to promoters to activate NF-κB transcription, and is reversible, since the complex disassembles before resolution of the program. Strikingly, we found that the ataxia telangiectasia mutated (ATM) kinase regulates the interaction between PPM1G and the 7SK snRNP through site-specific PPM1G phosphorylation. The precise and temporally regulated interaction of a cellular enzyme and a noncoding RNA provides a new paradigm for simultaneously controlling the activation and maintenance of inducible transcription elongation programs.
机译：转录延伸程序对于精确调节几种生物学过程至关重要。此类程序的一个主要调节因子是P-TEFb激酶，一旦从抑制性7SK小核糖核糖核蛋白（snRNP）复合物中释放出来，它就会磷酸化RNA聚合酶II（Pol II）。尽管P-TEFb从snRNP释放的机制变得越来越明确，但如何将P-TEFb保持在7SK未结合状态以维持转录延伸程序仍然未知。在这里我们报告说，一旦P-TEFb从7SK snRNP中释放出来，PPM1G磷酸酶（可被核因子κB[NF-κB]诱导募集到靶启动子）直接结合7SK RNA和激酶抑制剂Hexim1。 PPM1G的这种双重结合活性可阻止P-TEFb重组到snRNP上，以响应DNA损伤而维持NF-κB介导的Pol II转录。值得注意的是，PPM1G-7SK RNA相互作用是直接的，在动力学上遵循PPM1G向启动子募集以激活NF-κB转录，并且是可逆的，因为该复合物在程序解析之前会解体。惊人地，我们发现共济失调毛细血管扩张突变（ATM）激酶通过位点特异性PPM1G磷酸化调节PPM1G和7SK snRNP之间的相互作用。细胞酶和非编码RNA的精确和时间调控的相互作用为同时控制诱导型转录延伸程序的激活和维持提供了新的范例。

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