小柯机器人

美国威斯达研究所Ricky W. Johnstone、Stephin J. Vervoort等研究人员合作发现，PP2A-整合子-CDK9信号轴可微调转录，并用于癌症靶向治疗。这一研究成果于2021年5月17日在线发表在国际学术期刊《细胞》上。

研究人员发现CDK9介导的、RNA聚合酶II（RNAPII）驱动的转录在功能上受到蛋白质磷酸酶2A（PP2A）复合物的作用，该复合物由整合子复合物亚单位INTS6募集到转录位点。PP2A动态拮抗包括DSIF和RNAPII-CTD在内的关键CDK9底物的磷酸化。INTS6的丧失导致对CDK9抑制介导的肿瘤细胞死亡抵抗、CDK9磷酸底物的周转率降低以及急性致癌转录反应的扩增。药理学上的PP2A激活与CDK9抑制作用可协同杀死白血病和实体瘤细胞，从而在体内提供治疗益处。

这些数据表明，基因表达的精细控制依赖于整个转录周期中激酶和磷酸酶活性之间的平衡，该过程在癌症中失调，并可以用于治疗。

据悉，RNAPII的基因表达在转录周期中受到离散周期检查点中细胞周期蛋白依赖性激酶（CDK）的严格控制。转录起始后的暂停检查点主要由CDK9控制。

附：英文原文

Title: The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer

Author: Stephin J. Vervoort, Sarah A. Welsh, Jennifer R. Devlin, Elisa Barbieri, Deborah A. Knight, Sarah Offley, Stefan Bjelosevic, Matteo Costacurta, Izabela Todorovski, Conor J. Kearney, Jarrod J. Sandow, Zheng Fan, Benjamin Blyth, Victoria McLeod, Joseph H.A. Vissers, Karolina Pavic, Ben P. Martin, Gareth Gregory, Elena Demosthenous, Magnus Zethoven, Isabella Y. Kong, Edwin D. Hawkins, Simon J. Hogg, Madison J. Kelly, Andrea Newbold, Kaylene J. Simpson, Otto Kauko, Kieran F. Harvey, Michael Ohlmeyer, Jukka Westermarck, Nathanael Gray, Alessandro Gardini, Ricky W. Johnstone

Issue&Volume: 2021-05-17

Abstract: Gene expression by RNA polymerase II (RNAPII) is tightly controlled by cyclin-dependentkinases (CDKs) at discrete checkpoints during the transcription cycle. The pausingcheckpoint following transcription initiation is primarily controlled by CDK9. Wediscovered that CDK9-mediated, RNAPII-driven transcription is functionally opposedby a protein phosphatase 2A (PP2A) complex that is recruited to transcription sitesby the Integrator complex subunit INTS6. PP2A dynamically antagonizes phosphorylationof key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistanceto tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates,and amplification of acute oncogenic transcriptional responses. Pharmacological PP2Aactivation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells,providing therapeutic benefit in vivo. These data demonstrate that fine control of gene expression relies on the balancebetween kinase and phosphatase activity throughout the transcription cycle, a processdysregulated in cancer that can be exploited therapeutically.

DOI: 10.1016/j.cell.2021.04.022

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00502-X