RNA聚合酶Ⅱ启动子近端暂停的动态调控  

Dynamic regulation of promoter-proximal RNA polymerase Ⅱ pausing

作　　者：郭澄豪 罗卓娟[1] 林承棋[1] Chenghao Guo;Zhuojuan Luo;Chengqi Lin(Key Laboratory of Developmental Genes and Human Disease of Ministry of Education,School of Life Science and Technology,Southeast University,Nanjing 210096,China)

机构地区：[1]东南大学生命科学与技术学院,发育与疾病相关基因教育部重点实验室,南京210096

出　　处：《科学通报》2020年第35期4084-4094,共11页Chinese Science Bulletin

基　　金：国家重点研发计划(2018YFA0800100);国家自然科学基金(3197040262,31671343,31970626);江苏省自然科学基金(BK20170020)资助。

摘　　要：转录暂停是一种进化上保守的、从细菌到人类普遍存在的关键转录调控机制.在多数后生动物中,转录起始后, RNA聚合酶Ⅱ在发育和应激反应相关基因的启动子近端区域暂停,一旦受到环境或发育信号的刺激, RNA聚合酶Ⅱ从启动子近端向基因体释放,进行有效延伸. RNA聚合酶Ⅱ启动子近端暂停是转录的关键限速步骤之一,并作为转录早期检验点确保转录进程的正确运作.转录暂停和延伸调控异常与肿瘤及多种人类疾病密切相关.本文系统地从RNA聚合酶Ⅱ启动子近端暂停的建立、维持和释放等方面综述了对于这一重要转录限速步骤的调控,着重讨论了相分离通过浓缩和传递转录相关因子在调控Pol Ⅱ暂停和延伸过程中的作用,并展望了针对转录暂停和释放这一过程设计靶向性治疗策略的潜力.Transcriptional pausing is a widely used regulatory mechanism to control precise gene expression from bacteria to humans.In metazoans, transcription initiation requires the recruitment of general transcription factors and RNA polymerase Ⅱ(Pol Ⅱ) to gene promoters. After it initiates transcription and synthesizes a short RNA, Pol Ⅱ pauses at the promoter-proximal region, standing by for further cues to enter the productive elongation stage. Promoter-proximal Pol Ⅱ pausing is one of the rate-limiting steps during transcription, functioning as an early transcriptional elongation check point, to ensure the correct modification of transcription machinery and the addition of the 7-methylguanosine cap to nascent transcripts.Pol Ⅱ pausing at promoter-proximal region is stabilized by the negative elongation factor(NELF) and the 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole(DRB) sensitivity-inducing factor(DSIF). In response to developmental signals or environmental stress, the release of paused Pol Ⅱ can be triggered by the positive transcription elongation factor b(PTEFb), which is composed of the kinase CDK9 and its regulatory subunit CCNT1/2. The kinase activity of P-TEFb towards Pol Ⅱ carboxy-terminal domain(CTD), NELF and DSIF is critical for P-TEFb to execute its function in pause release, and is thus tightly controlled. To date, it has been identified that P-TEFb mainly exists in three different complexes:the super elongation complex(SEC), BRD4-P-TEFb, and the inactive 7 SK sn RNP-P-TEFb complex. SEC, one of the most active P-TEFb containing complexes, is required for rapid gene expression in response to stress or developmental signals.The active and inactive forms of P-TEFb complexes co-exist in vivo, reaching equilibrium to meet the transcriptional needs of cells. The transition of Pol Ⅱ from pause to productive elongation stage is achieved by dynamic exchange between the pausing factors and the positive elongation factors at the proximal promoter region.Liquid-liquid phase separation(LLPS) in li

关 键 词：RNA聚合酶Ⅱ 启动子近端暂停 转录延伸 超级转录延伸复合物 相分离 

分 类 号：Q753[生物学—分子生物学]