PNUTS/PP1 regulates RNAPII-mediated gene expression and is necessary for developmental growth.
PNUTS/PP1 regulates RNAPII-mediated gene expression and is necessary for developmental growth.
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DOI：
10.1371/journal.pgen.1003885
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发表时间：
2013-10
期刊：
影响因子：
4.5
通讯作者：
Bennett D
中科院分区：
文献类型：
--
作者：
Ciurciu A;Duncalf L;Jonchere V;Lansdale N;Vasieva O;Glenday P;Rudenko A;Vissi E;Cobbe N;Alphey L;Bennett D
在多细胞生物体中，基因表达的严格调控确保了整个发育过程中组织和生物体的适当生长。RNA聚合酶II（RNAPII）C-末端结构域（CTD）的可逆磷酸化对于基因表达状态的调节至关重要，但在发育背景下磷酸化如何被主动修饰仍然知之甚少。蛋白磷酸酶1（PP 1）是已报道的使RNAPII CTD去磷酸化的几种酶之一。然而，PP 1在动物发育过程中对转录调控的贡献以及其活性靶向RNAPII的机制尚未完全阐明。在这里，我们表明，果蝇直系同源的PP 1核靶向亚基（dPNUTS）是必不可少的有机体的发展，是细胞自主发展组织的生长所需的。dPNUTS在组织发育中的功能取决于它与PP 1的结合，我们发现PP 1是dPNUTS在染色体上许多转录活性位点与RNAPII结合的靶点。dPNUTS功能的丧失或其结合PP 1的能力的特异性破坏导致整个动物提取物和染色体上RNAPII CTD的过度磷酸化。与dPNUTS是一个全球性的转录调节因子相一致，我们发现dPNUTS功能的丧失会影响发育中的1龄幼虫中大多数基因的表达，包括促进增殖生长的基因。总之，这些发现揭示了PNUTS-PP 1全酶在体内的作用及其在果蝇早期发育过程中对基因表达控制的贡献。在发育过程中，细胞依赖于适当的基因表达模式来调节代谢，以满足细胞需求并保持快速的组织生长。相反，基因表达失调在各种疾病状态中至关重要，例如癌症和衰老期间。普遍用于控制基因表达的关键机制是可逆磷酸化，这是一种用于调节转录机制活性的分子开关。在这里，我们确定了一种酶，结合并调节磷酸化状态的RNA聚合酶II，一个核心组成部分的一般转录机制。我们还表明，这种酶的一个重要作用是支持正常的基因表达模式，促进生物体的生长。这些发现不仅与正常酶功能的理解有关，而且还可能有助于开发用于治疗衰老和疾病进展期间发生的基因表达异常模式的治疗策略。
In multicellular organisms, tight regulation of gene expression ensures appropriate tissue and organismal growth throughout development. Reversible phosphorylation of the RNA Polymerase II (RNAPII) C-terminal domain (CTD) is critical for the regulation of gene expression states, but how phosphorylation is actively modified in a developmental context remains poorly understood. Protein phosphatase 1 (PP1) is one of several enzymes that has been reported to dephosphorylate the RNAPII CTD. However, PP1's contribution to transcriptional regulation during animal development and the mechanisms by which its activity is targeted to RNAPII have not been fully elucidated. Here we show that the Drosophila orthologue of the PP1 Nuclear Targeting Subunit (dPNUTS) is essential for organismal development and is cell autonomously required for growth of developing tissues. The function of dPNUTS in tissue development depends on its binding to PP1, which we show is targeted by dPNUTS to RNAPII at many active sites of transcription on chromosomes. Loss of dPNUTS function or specific disruption of its ability to bind PP1 results in hyperphosphorylation of the RNAPII CTD in whole animal extracts and on chromosomes. Consistent with dPNUTS being a global transcriptional regulator, we find that loss of dPNUTS function affects the expression of the majority of genes in developing 1st instar larvae, including those that promote proliferative growth. Together, these findings shed light on the in vivo role of the PNUTS-PP1 holoenzyme and its contribution to the control of gene expression during early Drosophila development. During development, cells rely on appropriate patterns of gene expression to regulate metabolism in order to meet cellular demands and maintain rapid tissue growth. Conversely, dysregulation of gene expression is critical in various disease states, such as cancer, and during ageing. A key mechanism that is ubiquitously employed to control gene expression is reversible phosphorylation, a molecular switch that is used to regulate the activity of the transcriptional machinery. Here we identify an enzyme that binds to and regulates the phosphorylation state of RNA Polymerase II, a central component of the general transcription machinery. We also show that an essential role of this enzyme is to support normal patterns of gene expression that facilitate organismal growth. These findings are not only of relevance to the understanding of normal enzyme function but may also assist in the development of therapeutic strategies for the treatment of aberrant patterns of gene expression that occur during ageing and disease progression.
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影响因子：
12.3
作者：
Celniker SE;Wheeler DA;Kronmiller B;Carlson JW;Halpern A;Patel S;Adams M;Champe M;Dugan SP;Frise E;Hodgson A;George RA;Hoskins RA;Laverty T;Muzny DM;Nelson CR;Pacleb JM;Park S;Pfeiffer BD;Richards S;Sodergren EJ;Svirskas R;Tabor PE;Wan K;Stapleton M;Sutton GG;Venter C;Weinstock G;Scherer SE;Myers EW;Gibbs RA;Rubin GM
通讯作者：
Rubin GM
影响因子：
3.5
作者：
DOMBRADI, V;AXTON, JM;COHEN, PTW
通讯作者：
COHEN, PTW
影响因子：
3.9
作者：
du Puch, Christophe Bounaix Morand;Barbier, Ewa;Breton, Jean
通讯作者：
Breton, Jean
RNA 聚合酶 II C 端结构域的 Fcp1 去磷酸化是热休克基因有效转录所必需的
影响因子：
5.3
作者：
Fuda, Nicholas J.;Buckley, Martin S.;Lisa, John T.
通讯作者：
Lisa, John T.
影响因子：
3.6
作者：
De Leon, Gabriel;Sherry, Tara C.;Krucher, Nancy A.
通讯作者：
Krucher, Nancy A.