The Phantom Mark: Enigmatic roles of phospho-Threonine 4 modification of the C-terminal domain of RNA polymerase II.

IF 6.4 2区 生物学 Q1 CELL BIOLOGY Wiley Interdisciplinary Reviews: RNA Pub Date : 2023-07-01 Epub Date: 2023-01-06 DOI:10.1002/wrna.1771
Ryan P Kempen, Preeti Dabas, Aseem Z Ansari
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Abstract

The largest subunit of RNA polymerase II (Pol II) has an unusual carboxyl-terminal domain (CTD). This domain is composed of a tandemly repeating heptapeptide, Y1 S2 P3 T4 S5 P6 S7 , that has multiple roles in regulating Pol II function and processing newly synthesized RNA. Transient phosphorylation of Ser2 and Ser5 of the YS2 PTS5 PS repeat have well-defined roles in recruiting different protein complexes and coordinating sequential steps in gene transcription. As such, these phospho-marks encipher a molecular recognition code, colloquially termed the CTD code. In contrast, the contribution of phospho-Threonine 4 (pThr4/pT4) to the CTD code remains opaque and contentious. Fuelling the debate on the relevance of this mark to gene expression are the findings that replacing Thr4 with a valine or alanine has varied impact on cellular function in different species and independent proteomic analyses disagree on the relative abundance of pThr4 marks. Yet, substitution with negatively charged residues is lethal and even benign mutations selectively disrupt synthesis and 3' processing of distinct sets of coding and non-coding transcripts. Suggestive of non-canonical roles, pThr4 marked Pol II regulates distinct gene classes in a species- and signal-responsive manner. Hinting at undiscovered roles of this elusive mark, multiple signal-responsive kinases phosphorylate Thr4 at target genes. Here, we focus on this under-explored residue and postulate that the pThr4 mark is superimposed on the canonical CTD code to selectively regulate expression of targeted genes without perturbing genome-wide transcriptional processes. This article is categorized under: RNA Processing > 3' End Processing RNA Processing > Processing of Small RNAs RNA Processing > Splicing Regulation/Alternative Splicing.

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幻影标记:RNA 聚合酶 II C 端结构域磷酸苏氨酸 4 修饰的神秘作用。
RNA 聚合酶 II(Pol II)的最大亚基有一个不同寻常的羧基末端结构域(CTD)。该结构域由串联重复的七肽 Y1 S2 P3 T4 S5 P6 S7 组成,在调节 Pol II 功能和处理新合成的 RNA 方面具有多重作用。YS2 PTS5 PS 重复序列的 Ser2 和 Ser5 的瞬时磷酸化在招募不同的蛋白质复合物和协调基因转录的连续步骤方面具有明确的作用。因此,这些磷酸标记编码了一种分子识别代码,俗称 CTD 代码。与此相反,磷酸苏氨酸 4(pThr4/pT4)对 CTD 代码的贡献仍不明确,且存在争议。在不同物种中,用缬氨酸或丙氨酸取代 Thr4 对细胞功能的影响各不相同,而独立的蛋白质组分析也对 pThr4 标记的相对丰度存在分歧,这加剧了关于该标记与基因表达相关性的争论。然而,带负电荷残基的取代是致命的,即使是良性突变也会选择性地破坏不同编码和非编码转录本的合成和 3' 处理。pThr4标记的Pol II以物种和信号响应的方式调控不同的基因类别,这表明了它的非规范作用。多种信号反应激酶在靶基因上磷酸化 Thr4,暗示了这一难以捉摸的标记尚未被发现的作用。在这里,我们将重点放在这个未被充分探索的残基上,并推测 pThr4 标记叠加在标准 CTD 代码上,在不干扰全基因组转录过程的情况下选择性地调控目标基因的表达。本文归类于RNA 处理 > 3' 端处理 RNA 处理 > 小 RNA 的处理 RNA 处理 > 剪接调节/替代剪接。
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来源期刊
CiteScore
14.80
自引率
4.10%
发文量
67
审稿时长
6-12 weeks
期刊介绍: WIREs RNA aims to provide comprehensive, up-to-date, and coherent coverage of this interesting and growing field, providing a framework for both RNA experts and interdisciplinary researchers to not only gain perspective in areas of RNA biology, but to generate new insights and applications as well. Major topics to be covered are: RNA Structure and Dynamics; RNA Evolution and Genomics; RNA-Based Catalysis; RNA Interactions with Proteins and Other Molecules; Translation; RNA Processing; RNA Export/Localization; RNA Turnover and Surveillance; Regulatory RNAs/RNAi/Riboswitches; RNA in Disease and Development; and RNA Methods.
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