RNA 聚合酶 II (RNAPII) 转录周期的每个阶段都受到细胞周期蛋白依赖性蛋白激酶 (CDK) 和蛋白磷酸酶网络的调节。 RNAPII 从起始到终止的进展以 RPB1（其最大亚基）高度重复的羧基末端结构域 (CTD) 磷酸化模式的变化为标志，表明 CTD 代码的存在。与此同时，保守的转录延伸因子 SPT5（DRB 敏感性诱导因子 (DSIF) 的大亚基）在磷酸化状态中经历时空调节的变化，这可能与转录周期阶段之间的转换直接相关。在这里，我们回顾了最近从人类 SPT5 的结构、生化和遗传分析中获得的见解，这些分析表明它的两个磷酸化区域在转录的不同点发挥着不同的功能。灵活的RNA结合接头内的磷酸化促进启动子的释放——近端暂停——通常是基因表达中的限速步骤——而重复的羧基末端区域的修饰被认为有利于进行性延伸，并且在启动子启动前被去除。终止。两个基序的磷酸化均依赖于 CDK9，即正转录延伸因子 b (P-TEFb) 的催化亚基；它们在转录周期中在染色质上积累和功能的不同时间可能反映了它们被不同的磷酸酶去除、CDK9 磷酸化的不同动力学或两者兼而有之。 SPT5 调控的扰动通过很大程度上未知的机制对模型生物体的生存和发育产生深远影响，而修饰 SPT5 的酶已成为癌症的潜在治疗靶点；因此，阐明假定的 SPT5 代码是当务之急。版权所有 © 2024 Elsevier Ltd。保留所有权利。

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.Copyright © 2024 Elsevier Ltd. All rights reserved.