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A Cdk9-PPl switch regulates the elongation-termination transition of RNA polymerase Ⅱ

机译：Cdk9-PPl开关调节RNA聚合酶Ⅱ的延伸-终止转变

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The end of the RNA polymerase II (Pol II) transcription cycle is strictly regulated to prevent interference between neighbouring genes and to safeguard transcriptome integrity(1). The accumulation of Pol II downstream of the cleavage and polyadenylation signal can facilitate the recruitment of factors involved in mRNA 3'-end formation and termination(2), but how this sequence is initiated remains unclear. In a chemical-genetic screen, human protein phosphatase 1 (PP1) isoforms were identified as substrates of positive transcription elongation factor b (P-TEFb), also known as the cyclin-dependent kinase 9 (Cdk9)-cyclin T1 (CycT1) complex(3). Here we show that Cdk9 and PP1 govern phosphorylation of the conserved elongation factor Spt5 in the fission yeast Schizosaccharomyces pombe. Cdk9 phosphorylates both Spt5 and a negative regulatory site on the PP1 isoform Dis2(4). Sites targeted by Cdk9 in the Spt5 carboxy-terminal domain can be dephosphorylated by Dis2 in vitro, and dis2 mutations retard Spt5 dephosphorylation after inhibition of Cdk9 in vivo. Chromatin immunoprecipitation and sequencing analysis indicates that Spt5 is dephosphorylated as transcription complexes traverse the cleavage and polyadenylation signal, concomitant with the accumulation of Pol II phosphorylated at residue Ser2 of the carboxy-terminal domain consensus heptad repeats. A conditionally lethal Dis2-inactivating mutation attenuates the drop in Spt5 phosphorylation on chromatin, promotes transcription beyond the normal termination zone (as detected by precision run-on transcription and sequencing(6)) and is genetically suppressed by the ablation of Cdk9 target sites in Spt5. These results suggest that the transition of Pol II from elongation to termination coincides with a Dis2-dependent reversal of Cdk9 signalling-a switch that is analogous to a Cdkl-PP1 circuit that controls mitotic progression(4).
机译：严格调节RNA聚合酶II（Pol II）转录周期的末端，以防止相邻基因之间的干扰并维护转录组完整性（1）。裂解和聚腺苷酸化信号下游的Pol II的积累可以促进募集参与mRNA 3'末端形成和终止的因子（2），但该序列如何启动尚不清楚。在化学遗传筛选中，人类蛋白磷酸酶1（PP1）亚型被鉴定为正转录延伸因子b（P-TEFb）的底物，也称为细胞周期蛋白依赖性激酶9（Cdk9）-细胞周期蛋白T1（CycT1）复合物（3）。在这里，我们显示Cdk9和PP1控制裂变酵母粟酒裂殖酵母中保守的延伸因子Spt5的磷酸化。 Cdk9磷酸化Spt5和PP1亚型Dis2（4）上的负调控位点。在体外，Dis2可以将Spd5羧基末端结构域中Cdk9靶向的位点去磷酸化，而在体内抑制Cdk9后，dis2突变会延迟Spt5的去磷酸化。染色质的免疫沉淀和测序分析表明，随着转录复合物穿过切割和聚腺苷酸化信号，Spt5被去磷酸化，同时在羧基末端结构域共有七聚体重复序列的Ser2残基处磷酸化的Pol II积累。有条件地致死的Dis2失活突变减弱了染色质上Spt5磷酸化的下降，促进了转录到正常终止区域之外（通过精确的连续转录和测序检测（6）），并在基因上被Cdk9靶位点的切除抑制了遗传。 Spt5。这些结果表明，Pol II从伸长到终止的转变与Cdk9信号的Dis2依赖性逆转相吻合-类似于控制有丝分裂进程的Cdkl-PP1电路的开关（4）。

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  • 来源
    《Nature》 |2018年第7710期|460-464|共5页
  • 作者

    Parua Pabitra K.; Booth Gregory T.; Sanso Miriam; Benjamin Bradley; Tanny Jason C.; Lis John T.; Fisher Robert P.;

  • 作者单位

    Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA;

    Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA;

    Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA;

    Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA;

    McGill Univ, Dept Pharmacol & Therapeut, Montreal, PQ, Canada;

    Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA;

    Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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