RNAPII控制转录伸长的CDK9-SPT5轴
The CDK9-SPT5 Axis in Control of Transcription Elongation by RNAPII
影响因子:4.50000
分区:生物学2区 / 生化与分子生物学3区
发表日期:2025 Jan 01
作者:
Rui Sun, Robert P Fisher
摘要
RNA聚合酶II（RNAPII）转录周期在每个阶段都通过细胞周期蛋白依赖性蛋白激酶（CDK）和蛋白质磷酸酶的网络来调节。 RNAPII从启动到终止的进展标志着RPB1（其最大的亚基）高度重复的羧基末端域（CTD）的磷酸化模式的变化，这表明存在CTD代码。同时，保守的转录伸长因子SPT5，DRB敏感性诱导因子（DSIF）的较大亚基，经历了磷酸化状态的时空调节变化，这些变化可能直接与转录周期相之间的过渡直接相关。在这里，我们回顾了人类SPT5的最新结构，生化和遗传分析所获得的见解，这些结构，生化和遗传分析表明，其两个磷酸化区域在不同转录点的不同点具有不同的功能。柔性，RNA结合链接器内的磷酸化促进了从启动子 - 偶然暂停的释放，通常会在重复的羧基末端区域中的基因表达速率变化速率限制步骤，从而被认为是有利于过程伸长的，并且在终止之前被删除。两个基序中的磷酸化依赖于CDK9，阳性转录伸长因子B（P-TEFB）的催化亚基；它们在转录周期中在染色质和功能上积累的不同时间可能反映出它们通过不同的磷酸酶，CDK9或两者兼而有之的不同磷酸化动力学。 SPT5调节的扰动对模型生物的生存力和开发具有深远的影响，而在很大程度上未知机制，而改变SPT5的酶已成为癌症的潜在治疗靶标。因此，阐明推定的SPT5代码是一个很高的优先级。
Abstract
The RNA polymerase II (RNAPII) transcription cycle is regulated at every stage by a network of cyclin-dependent protein kinases (CDKs) and protein phosphatases. Progression of RNAPII from initiation to termination is marked by changing patterns of phosphorylation on the highly repetitive carboxy-terminal domain (CTD) of RPB1, its largest subunit, suggesting the existence of a CTD code. In parallel, the conserved transcription elongation factor SPT5, large subunit of the DRB sensitivity-inducing factor (DSIF), undergoes spatiotemporally regulated changes in phosphorylation state that may be directly linked to the transitions between transcription-cycle phases. Here we review insights gained from recent structural, biochemical, and genetic analyses of human SPT5, which suggest that two of its phosphorylated regions perform distinct functions at different points in transcription. Phosphorylation within a flexible, RNA-binding linker promotes release from the promoter-proximal pause-frequently a rate-limiting step in gene expression-whereas modifications in a repetitive carboxy-terminal region are thought to favor processive elongation, and are removed just prior to termination. Phosphorylations in both motifs depend on CDK9, catalytic subunit of positive transcription elongation factor b (P-TEFb); their different timing of accumulation on chromatin and function during the transcription cycle might reflect their removal by different phosphatases, different kinetics of phosphorylation by CDK9, or both. Perturbations of SPT5 regulation have profound impacts on viability and development in model organisms through largely unknown mechanisms, while enzymes that modify SPT5 have emerged as potential therapeutic targets in cancer; elucidating a putative SPT5 code is therefore a high priority.