TFIIE orchestrates the recruitment of the TFIIH kinase module at promoter before release during transcription

Compe, Emmanuel; Robles, Carlos Mario Genes; Braun, Cathy; Coin, Frédéric; Egly, Jean‐Marc

doi:10.1038/s41467-019-10131-1

Cited by 42 publications

(39 citation statements)

References 63 publications

(76 reference statements)

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“…For example, Tat recruits TBP to the HIV-1 LTR in the absence of other TFIID components, such as TAFs, through an interaction with P-TEFb [39]. PIC assembly is completed by recruitment of RNAPII and the final general transcription factors, TFIIE and TFIIH [134,135].…”

Section: Early Stages Of Transcriptionmentioning

confidence: 99%

Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure

Mori¹,

Valente²

2020

Viruses

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HIV-1 establishes a life-long infection when proviral DNA integrates into the host genome. The provirus can then either actively transcribe RNA or enter a latent state, without viral production. The switch between these two states is governed in great part by the viral protein, Tat, which promotes RNA transcript elongation. Latency is also influenced by the availability of host transcription factors, integration site, and the surrounding chromatin environment. The latent reservoir is established in the first few days of infection and serves as the source of viral rebound upon treatment interruption. Despite effective suppression of HIV-1 replication by antiretroviral therapy (ART), to below the detection limit, ART is ineffective at reducing the latent reservoir size. Elimination of this reservoir has become a major goal of the HIV-1 cure field. However, aside from the ideal total HIV-1 eradication from the host genome, an HIV-1 remission or functional cure is probably more realistic. The “block-and-lock” approach aims at the transcriptional silencing of the viral reservoir, to render suppressed HIV-1 promoters extremely difficult to reactivate from latency. There are unfortunately no clinically available HIV-1 specific transcriptional inhibitors. Understanding the mechanisms that regulate latency is expected to provide novel targets to be explored in cure approaches.

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Section: Early Stages Of Transcriptionmentioning

confidence: 99%

Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure

Mori¹,

Valente²

2020

Viruses

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“…The heterodimeric general transcription factor TFIIE recruits TFIIH to the preinitiation complex of RNA polymerase II promoters and is thus involved in gene expression of all protein-coding genes (Compe et al, 2019, Ohkuma, Sumimoto et al, 1990). Here we describe an unanticipated role of TFIIE which profoundly impairs ribosomal biogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in TFIIH cause the photosensitive form of the multisystem disorder trichothiodystrophy (TTD), a syndrome with delayed development, microcephaly, neurological degeneration, recurrent, infections and eponymous skin and hair abnormalities. TTD is mainly attributed to a transcription syndrome (Compe, Genes et al, 2019, Theil, Mandemaker et al, 2017). However, recently discovered mutations in aminoacyl-tRNA synthetases that result in TTD may shift this classification towards a “gene expression syndrome” referred to a disturbed protein translation at the ribosome (Kuo, Theil et al, 2019, Theil, Botta et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Nucleolar TFIIE plays a role in ribosomal biogenesis and performance

Phan

Maity

Ludwig³

et al. 2020

Preprint

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Ribosome biogenesis is a highly energy-demanding process in eukaryotes which requires the concerted action of all three RNA polymerases. In RNA polymerase II transcription, the general transcription factor TFIIH is recruited by TFIIE to the initiation site of protein-coding genes. Distinct mutations in TFIIH and TFIIE give rise to the degenerative disorder trichothiodystrophy (TTD). Here we uncovered an unexpected role of TFIIE in ribosomal RNA synthesis by RNA polymerase I. With high resolution microscopy we detected TFIIE in the nucleolus where TFIIE binds to actively transcribed rDNA. Mutations in TFIIE affects gene-occupancy of RNA polymerase I, rRNA maturation, ribosomal assembly and performance. In consequence, the elevated translational error rate with imbalanced protein synthesis and turnover results in an increase in heat-sensitive proteins. Collectively, mutations in TFIIE - due to impaired ribosomal biogenesis and translational accuracy - lead to a loss of protein homeostasis (proteostasis) which can partly explain the clinical phenotype in TTD.

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“…Previous studies have reported that the carboxy-terminal domain (CTD) of the largest subunit of RNA Pol II is a canonical direct substrate of the CAK complex, and that the phosphorylation of RNA Pol II Ser 5 and Ser 7 residues is primarily mediated by CDK7 activity [19,36,37]. Therefore, we evaluated CAK activity in cells exposed to VP1 through quantification of RNA Pol II CTD Ser 5 phosphorylation levels.…”

Section: Cvb3 Vp1-mat1 Interaction Suppresses Cak Activity Via Cdk7 Imentioning

confidence: 99%

“…MAT1 is required for functional CAK assembly and induces CDK7 kinase activity [18]. However, TFIIH depends on CDK7 activity to play its role in transcriptional initiation [19,20]. CDK7 has been revealed to perform dual functions, contributing a central role in the enzymatic activity of the CAK complex while also regulating transcription through phosphorylation of RNA polymerase II and transcription factors [8,21,22].…”

Section: Introductionmentioning

confidence: 99%

CVB3 VP1 interacts with MAT1 to inhibit cell proliferation by interfering with Cdk-activating kinase complex activity in CVB3-induced acute pancreatitis

Zhang

Zeng

Liu

et al. 2020

Preprint

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Coxsackievirus B3 (CVB3) belongs to the genus Enterovirus of the family Picornaviridae and can cause acute acinar pancreatitis in adults. However, the molecular mechanisms of pathogenesis underlying CVB3-induced acute pancreatitis have remained unclear. In this study, we discovered that CVB3 capsid protein VP1 inhibited pancreatic cell proliferation and exerted strong cytopathic effects on HPAC cells. Through yeast two-hybrid, co-immunoprecipitation, and confocal microscopy, we show that Menage a trois 1 (MAT1), a subunit of the Cdk-Activating Kinase (CAK) complex involved in cell proliferation and transcription, is a novel interaction protein with CVB3 VP1. Moreover, CVB3 VP1 inhibited MAT1 accumulation and localization, thus interfering with its interaction with CDK7. Furthermore, CVB3 VP1 could suppress CAK complex enzymic phosphorylation activity towards RNA Pol II and CDK4/6, direct substrates of CAK. VP1 also suppresses phosphorylation of retinoblastoma protein (pRb), an indirect CAK substrate, especially at phospho-pRb Ser780 and phospho-pRb Ser807/811 residues, which are associated with cell proliferation. Finally, we present evidence using deletion mutants that the C-terminal domain (VP1-D8, 768-859aa) is the minimal VP1 region required for its interaction with MAT1, and furthermore, VP1-D8 alone was sufficient to arrest cells in G1/S phase as observed during CVB3 infection. Taken together, we demonstrate that CVB3 VP1 can inhibit CAK complex assembly and activity through direct interaction with MAT1, to block MAT1-mediated CAK-CDK4/6-Rb signaling, and ultimately suppress cell proliferation in pancreatic cells. These findings substantially extend our basic understanding of CVB3-mediated pancreatitis, providing strong candidates for strategic therapeutic targeting.

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TFIIE orchestrates the recruitment of the TFIIH kinase module at promoter before release during transcription

Cited by 42 publications

References 63 publications

Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure

Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure

Nucleolar TFIIE plays a role in ribosomal biogenesis and performance

CVB3 VP1 interacts with MAT1 to inhibit cell proliferation by interfering with Cdk-activating kinase complex activity in CVB3-induced acute pancreatitis

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