Review

RNAPII转录延伸控制中的CDK9-SPT5轴研究

The CDK9-SPT5 Axis in Control of Transcription Elongation by RNAPII

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JOURNAL OF MOLECULAR BIOLOGY

影响因子:4.5

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

DOI: 10.1016/j.jmb.2024.168746

摘要

RNA聚合酶II（RNAPII）的转录周期在每个阶段都受到周期蛋白依赖性蛋白激酶（CDKs）和蛋白磷酸酶网络的调控。RNAPII从起始到终止的过程由其最大亚基RPB1的高度重复的羧基末端结构域（CTD）上磷酸化模式的变化所标志，暗示存在CTD密码。同时，保守的转录延伸因子SPT5（DRB敏感性诱导因子（DSIF）的大亚基）也经历时空调控的磷酸化状态变化，这可能与转录周期不同阶段的转换直接相关。本文回顾了近期对人类SPT5的结构、生化和遗传分析的见解，表明其两个磷酸化区域在转录的不同阶段执行不同的功能。一个灵活的、RNA结合的连接子中的磷酸化促进从启动子邻近暂停的释放——这是基因表达中的一个速率限制步骤——而重复的羧基末端区域的修饰则可能促进连续延伸，并在终止前被移除。两个基序中的磷酸化均依赖于CDK9，即正转录延伸因子b（P-TEFb）的催化亚基；它们在染色质上的积累时间和在转录周期中的功能差异，可能反映了它们被不同的磷酸酶去除、由CDK9的不同动力学磷酸化，或两者兼而有之。SPT5调控的扰动在模式生物中对生存和发育具有深远影响，其机制尚未完全揭示，而修饰SPT5的酶已成为癌症治疗的潜在靶点；阐明潜在的SPT5密码因此成为当前的研究重点。

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.