The RNAPII-CTD at the nexus of general and gene-specific regulation of transcription

RNAPII-CTD 处于一般转录调控和基因特异性转录调控的关系中

• 批准号: RGPIN-2016-04297
• 负责人: Kobor, Michael
• 金额: $ 3.21万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709086
• 关键词: RNAPII; CTD; nexus; general; gene

DNA contains the information necessary for life and accurate reading of this material is essential to adapt to changing environments. This is accomplished though a processed called transcription, during which the cell selects the genetic information to be read. RNA Polymerase II (RNAPII) is the molecular machine responsible for most transcription in the cell. It contains an extended region called the C-terminal domain (CTD). The CTD is important for all RNAPII-dependent transcription, given that it function as a platform for recruiting auxiliary factors required for this process. This activity is dependent on timely deposition and removal of modifications on the CTD. For example, the CTD modification status at the beginning of transcription differs from that of the end, allowing RNAPII to recruit specific factors at different stages of the process. The CTD is modified through the coordinated action of a number of enzymes in the cell, including Fcp1 and Cdk8. Fcp1 generally functions in recycling RNAPII by removing all CTD modifications following the end of transcription. This RNAPII can then be targeted by Cdk8, which blocks it from starting additional rounds of transcription, by prematurely modifying its CTD. As such, Fcp1 and Cdk8 play important roles in regulating the availability of RNAPII for transcription. Previously it was shown that shortening the CTD results in incorrect reading of genomic information, impaired ability to adapt to changing environments, altered CTD modification patters, and altered recruitment of factors necessary during transcription. Interestingly, the work described above also showed that while some of these effects were observed across all transcriptional units, others were confined to a smaller subset, switching our view of the RNAP-CTD as exclusively performing general functions, to being able to integrate regulatory signals in a specific manner. Our recent investigation of Fcp1 yielded similar findings as it revealed specific functions during transcription as it relates to the adaptation to high temperature and salt conditions. Here, we propose to tease apart general vs. specific functions of the RNAPII-CTD and Fcp1, and to identify factors and pathways that communicate with them to ensure correct reading of genetic information.

DNA 包含生命所需的信息，准确读取这种材料对于适应不断变化的环境至关重要。这是通过称为转录的过程来完成的，在此过程中细胞选择要读取的遗传信息。 RNA 聚合酶 II (RNAPII) 是负责细胞内大部分转录的分子机器。它包含一个称为 C 端结构域 (CTD) 的扩展区域。 CTD 对于所有 RNAPII 依赖性转录都很重要，因为它充当招募该过程所需的辅助因子的平台。此活动依赖于 CTD 上修改的及时沉积和去除。例如，转录开始时和结束时的CTD修饰状态不同，使得RNAPII能够在该过程的不同阶段招募特定因子。 CTD 通过细胞中多种酶（包括 Fcp1 和 Cdk8）的协调作用进行修改。 Fcp1 通常通过去除转录结束后的所有 CTD 修饰来回收 RNAPII。然后，Cdk8 可以靶向该 RNAPII，Cdk8 通过过早修改其 CTD 来阻止其启动额外的转录轮次。因此，Fcp1 和 Cdk8 在调节 RNAPII 转录的可用性方面发挥着重要作用。 之前的研究表明，缩短 CTD 会导致基因组信息的错误读取、适应环境变化的能力受损、CTD 修饰模式改变以及转录过程中必需因子的招募发生改变。有趣的是，上述工作还表明，虽然在所有转录单位中都观察到了其中一些效应，但其他效应仅限于较小的子集，这将我们对 RNAP-CTD 的看法转变为专门执行一般功能，以能够以特定方式整合调节信号。我们最近对 Fcp1 的研究得到了类似的发现，因为它揭示了转录过程中与适应高温和盐条件有关的特定功能。在这里，我们建议区分 RNAPII-CTD 和 Fcp1 的一般功能和特定功能，并确定与它们通信的因子和途径，以确保正确读取遗传信息。