Ras and Rho GTPase regulation of Pol II transcription: A shortcut model revisited

Zheng, Zhi‐Liang

doi:10.1080/21541264.2017.1321612

Cited by 3 publications

(5 citation statements)

References 42 publications

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“…The transcriptional procedure is mediated by Ras and Rho family small GTPases to alter gene expression. It has been well documented that an evolutionarily conserved Rho GTPase signaling pathway that targets proteasomes as CTD phosphatases can directly modify the RNA Pol II CTD [ 27 , 28 ]. Indeed, a previous study reported that Rho family GTPases, such as CDC42, can alter the phosphorylation of Ser2 and Ser5 in the CTD of RPB1, the largest subunit of Pol II, thereby affecting gene expression and influencing the size, shape, and number of cells [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Super-Resolution Microscopy Analysis of Hepatitis B Viral cccDNA and Host Factors

Doan

Nio

Shimakami

et al. 2023

Viruses

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Infection with hepatitis B virus (HBV) cannot be cured completely because of the persistence of covalently closed circular DNA (cccDNA). We previously found that the host gene dedicator of cytokinesis 11 (DOCK11) was required for HBV persistence. In this study, we further investigated the mechanism that links DOCK11 to other host genes in the regulation of cccDNA transcription. cccDNA levels were determined by quantitative real-time polymerase chain reaction (qPCR) and fluorescence in situ hybridization (FISH) in stable HBV-producing cell lines and HBV-infected PXB-cells®. Interactions between DOCK11 and other host genes were identified by super-resolution microscopy, immunoblotting, and chromatin immunoprecipitation. FISH facilitated the subcellular localization of key HBV nucleic acids. Interestingly, although DOCK11 partially colocalized with histone proteins, such as H3K4me3 and H3K27me3, and nonhistone proteins, such as RNA Pol II, it played limited roles in histone modification and RNA transcription. DOCK11 was functionally involved in regulating the subnuclear distribution of host factors and/or cccDNA, resulting in an increase in cccDNA closely located to H3K4me3 and RNA Pol II for activating cccDNA transcription. Thus, it was suggested that the association of cccDNA-bound Pol II and H3K4me3 required the assistance of DOCK11. DOCK11 facilitated the association of cccDNA with H3K4me3 and RNA Pol II.

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Section: Discussionmentioning

confidence: 99%

Super-Resolution Microscopy Analysis of Hepatitis B Viral cccDNA and Host Factors

Doan

Nio

Shimakami

et al. 2023

Viruses

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“…How these kinases and phosphatases are controlled by upstream signals in gene expression regulation have received increasing attention. Accumulating evidence suggests the existence of two models of transcriptional control ( Figure 4 ) [ 54 ]. In the “ classical ” model of transcriptional control, which is frequently described in molecular genetics or cell biology textbooks, extracellular proliferation cues first activate intracellular signaling switches, such as the well-studied Ras and Rho families of small GTPases, which in turn activate the MAP kinase cascade.…”

Section: Functional Conservation Of Cdk and Ctd Phosphatasesmentioning

confidence: 99%

“…In the “ classical ” model of transcriptional control, which is frequently described in molecular genetics or cell biology textbooks, extracellular proliferation cues first activate intracellular signaling switches, such as the well-studied Ras and Rho families of small GTPases, which in turn activate the MAP kinase cascade. Subsequently, phosphorylated MAPKs phosphorylate various sequence-specific transcription factors, which then become active and bind to the gene-specific enhancer and consequently, recruit Pol II, by interacting with the general transcription factor TFIIH complex, to the core promoter of those genes to be transcribed [ 54 ]. Moreover, this interaction stimulates Ser5P in the CTD of RPB1 via activation of CDK7 present in the general transcription factor TFIIH complex and/or the mediator complex [ 55 , 56 , 57 ].…”

Section: Functional Conservation Of Cdk and Ctd Phosphatasesmentioning

confidence: 99%

Cyclin-Dependent Kinases and CTD Phosphatases in Cell Cycle Transcriptional Control: Conservation across Eukaryotic Kingdoms and Uniqueness to Plants

Zheng

2022

Cells

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Cell cycle control is vital for cell proliferation in all eukaryotic organisms. The entire cell cycle can be conceptually separated into four distinct phases, Gap 1 (G1), DNA synthesis (S), G2, and mitosis (M), which progress sequentially. The precise control of transcription, in particular, at the G1 to S and G2 to M transitions, is crucial for the synthesis of many phase-specific proteins, to ensure orderly progression throughout the cell cycle. This mini-review highlights highly conserved transcriptional regulators that are shared in budding yeast (Saccharomyces cerevisiae), Arabidopsis thaliana model plant, and humans, which have been separated for more than a billion years of evolution. These include structurally and/or functionally conserved regulators cyclin-dependent kinases (CDKs), RNA polymerase II C-terminal domain (CTD) phosphatases, and the classical versus shortcut models of Pol II transcriptional control. A few of CDKs and CTD phosphatases counteract to control the Pol II CTD Ser phosphorylation codes and are considered critical regulators of Pol II transcriptional process from initiation to elongation and termination. The functions of plant-unique CDKs and CTD phosphatases in relation to cell division are also briefly summarized. Future studies towards testing a cooperative transcriptional mechanism, which is proposed here and involves sequence-specific transcription factors and the shortcut model of Pol II CTD code modulation, across the three eukaryotic kingdoms will reveal how individual organisms achieve the most productive, large-scale transcription of phase-specific genes required for orderly progression throughout the entire cell cycle.

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“…Ras superfamily small GTPases, including Ras and Rho families, act as key signaling switches in regulating gene expression, and consequently deregulation of these signaling GTPases is frequently associated with many diseases including cancer [1][2][3][4][5]. There are two models regarding Ras and Rho GTPase control of RNA polymerase (Pol) II transcription: the well-known classical or "indirect" model, and the recently re-emerged direct or "shortcut" model [6]. The classical model has been described in genetics and cell biology textbooks and literature and presented as a paradigm in oncogenic signaling networks.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, the shortcut model allows activated GTPases to target protein kinase A or proteasome to regulate a component of Mediator [7] or Pol II [8]. Given that the shortcut model does not involve the MAP kinase cascade and instead directly regulates Pol II or its components, this model has a potential of efficiently regulating transcription so as to rapidly bring about the broad changes in gene expression in response to dynamic intracellular and extracellular changes [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Modulation of the Pol II CTD Phosphorylation Code by Rac1 and Cdc42 Small GTPases in Cultured Human Cancer Cells and Its Implication for Developing a Synthetic-Lethal Cancer Therapy

Zhang¹,

Zhong²,

Sauane³

et al. 2020

Cells

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Rho GTPases, including Rho, Cdc42, Rac and ROP subfamilies, are key signaling molecules in RNA polymerase II (Pol II) transcriptional control. Our prior work has shown that plant ROP and yeast Cdc42 GTPases similarly modulate Ser2 and Ser5 phosphorylation status of the C-terminal domain (CTD) of the Pol II largest subunit by regulating CTD phosphatase degradation. Here, we present genetic and pharmacological evidence showing that Cdc42 and Rac1 GTPase signaling modulates a similar CTD Ser2 and Ser5 phosphorylation code in cultured human cancer cells. While siRNA knockdown of Cdc42 and Rac1, respectively, in HeLa cells increased the level of CTD Ser phosphatases RPAP2 and FCP1, they both decreased the level of CTD kinases CDK7 and CDK13. In addition, the protein degradation inhibitor MG132 reversed the effect of THZ1, a CDK7 inhibitor which could decrease the cell number and amount of CDK7 and CDK13, accompanied by a reduction in the level of CTD Ser2 and Ser5 phosphorylation and DOCK4 and DOCK9 (the activators for Rac1 and Cdc42, respectively). Conversely, treatments of Torin1 or serum deprivation, both of which promote protein degradation, could enhance the effect of THZ1, indicating the involvement of protein degradation in controlling CDK7 and CDK13. Our results support an evolutionarily conserved signaling shortcut model linking Rho GTPases to Pol II transcription across three kingdoms, Fungi, Plantae and Animalia, and could lead to the development of a potential synthetic-lethal strategy in controlling cancer cell proliferation or death.

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Ras and Rho GTPase regulation of Pol II transcription: A shortcut model revisited

Cited by 3 publications

References 42 publications

Super-Resolution Microscopy Analysis of Hepatitis B Viral cccDNA and Host Factors

Super-Resolution Microscopy Analysis of Hepatitis B Viral cccDNA and Host Factors

Cyclin-Dependent Kinases and CTD Phosphatases in Cell Cycle Transcriptional Control: Conservation across Eukaryotic Kingdoms and Uniqueness to Plants

Modulation of the Pol II CTD Phosphorylation Code by Rac1 and Cdc42 Small GTPases in Cultured Human Cancer Cells and Its Implication for Developing a Synthetic-Lethal Cancer Therapy

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