Cell-type specific concentration regulation of the basal transcription factor TFIIH in XPBy/y mice model

Donnio, Lise-Marie; Miquel, Catherine; Vermeulen, Wim; Giglia-Mari, Giuseppina; Mari, Pierre-Olivier

doi:10.1186/s12935-019-0945-4

Cited by 7 publications

(2 citation statements)

References 37 publications

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“…As nuclei in neurons are smaller than those in oocytes, hypodermal and intestinal cells, the TFIIH concentration will also be lower in these cell types. Similar analysis of mouse XPB-YFP fluorescence levels in tissues of XPB-YFP knockin mice also showed that TFIIH levels vary depending on the cell type, which, interestingly, was found to correlate to transcriptional activity in these cells (Donnio et al , 2019). Thus, possibly also in C. elegans TFIIH levels can be used as quantitative biomarker of transcriptional activity.…”

Section: Resultsmentioning

confidence: 65%

C. elegansTFIIH subunit GTF-2H5/TTDA is a non-essential transcription factor indispensable for DNA repair

Thijssen

Woude

Davó-Martínez

et al. 2021

Preprint

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The 10-subunit TFIIH complex is vital to both transcription initiation and nucleotide excision repair. Hereditary mutations in its smallest subunit, TTDA/GTF2H5, cause a photosensitive form of the rare developmental brittle hair disorder trichothiodystrophy (TTD). Some TTD features are thought to be caused by subtle transcription or gene expression defects. Strikingly, TTDA/GTF2H5 knockout mice are not viable, which makes it difficult to investigate how TTDA/GTF2H5 promotes transcription in vivo. Here, we show that deficiency of the C. elegans TTDA ortholog GTF-2H5 is, however, compatible with viability and growth, in contrast to depletion of other TFIIH subunits. We also show that GTF-2H5 promotes the stability of TFIIH in multiple tissues and is indispensable for nucleotide excision repair, in which it facilitates recruitment of the TFIIH complex to DNA damage. Strikingly, when transcription is challenged, gtf-2H5 embryos die due to the intrinsic TFIIH fragility in the absence of GTF-2H5. These results support the idea that TTDA/GTF2H5 mutations cause transcription impairment underlying trichothiodystrophy and establish C. elegans as potential model for studying the pathogenesis of this disease.

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Section: Resultsmentioning

confidence: 65%

C. elegansTFIIH subunit GTF-2H5/TTDA is a non-essential transcription factor indispensable for DNA repair

Thijssen

Woude

Davó-Martínez

et al. 2021

Preprint

Self Cite

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“…It is proposed that FUSE and FIR binding to TFIIH regulates activation-dependent, but not basal MYC expression (82). The level of TFIIH in cells is tightly regulated and correlates with transcriptional activity (84). Thus, we expect that inducible genes that become transcriptionally very active upon stimulation may be more susceptible to XPB degradation than those transcribed at a far lower rate.…”

Section: Downloaded Frommentioning

confidence: 99%

The XPB Subunit of the TFIIH Complex Plays a Critical Role in HIV-1 Transcription, and XPB Inhibition by Spironolactone Prevents HIV-1 Reactivation from Latency

Mori

Jenike

Yeh

et al. 2021

J Virol

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HIV transcription requires assembly of cellular transcription factors at the HIV-1promoter. The TFIIH general transcription factor facilitates transcription initiation by opening the DNA strands around the transcription start site and phosphorylating the C-terminal domain for RNA polymerase II (RNAPII) for activation. Spironolactone (SP), an FDA approved aldosterone antagonist, triggers the proteasomal degradation of the XPB subunit of TFIIH, and concurrently suppresses acute HIV infection in vitro. Here we investigated SP as a possible block-and-lock agent for a functional cure aimed at the transcriptional silencing of the viral reservoir. The long-term activity of SP was investigated in primary and cell line models of HIV-1 latency and reactivation. We show that SP rapidly inhibits HIV-1 transcription by reducing RNAPII recruitment to the HIV-1 genome. shRNA knockdown of XPB confirmed XPB degradation as the mechanism of action. Unfortunately, long-term pre-treatment with SP does not result in epigenetic suppression of HIV upon SP treatment interruption, since virus rapidly rebounds when XPB reemerges; however, SP alone without ART maintains the transcriptional suppression. Importantly, SP inhibits HIV reactivation from latency in both cell line models and resting CD4+T cells isolated from aviremic infected individuals upon cell stimulation with latency reversing agents. Furthermore, long-term treatment with concentrations of SP that potently degrade XPB does not lead to global dysregulation of cellular mRNA expression. Overall, these results suggest that XPB plays a key role in HIV transcriptional regulation and XPB degradation by SP strengthens the potential of HIV transcriptional inhibitors in block-and-lock HIV cure approaches. IMPORTANCE Antiretroviral therapy (ART) effectively reduces an individual’s HIV loads to below the detection limit, nevertheless rapid viral rebound immediately ensues upon treatment interruption. Furthermore, virally suppressed individuals experience chronic immune activation from ongoing low-level virus expression. Thus, the importance of identifying novel therapeutics to explore in block-and-lock HIV functional cure approaches, aimed at the transcriptional and epigenetic silencing of the viral reservoir to block reactivation from latency. We investigated the potential of repurposing the FDA-approved spironolactone (SP), as one such drug. SP treatment rapidly degrades a host transcription factor subunit, XPB, inhibiting HIV transcription and blocking reactivation from latency. Long-term SP treatment does not affect cellular viability, cell cycle progression or global cellular transcription. SP alone blocks HIV transcription in the absence of ART but does not delay rebound upon drug removal as XPB rapidly reemerges. This study highlights XPB as a novel drug target in block-and-lock therapeutic approaches.

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Growth factor-loaded ovarian extracellular matrix hydrogels promote in vivo ovarian niche regeneration and enhance fertility in premature ovarian insufficiency preclinical models

Francés-Herrero,

Bueno-Fernandez,

Rodríguez-Eguren

et al. 2024

Acta Biomaterialia

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Cell-type specific concentration regulation of the basal transcription factor TFIIH in XPBy/y mice model

Cited by 7 publications

References 37 publications

C. elegansTFIIH subunit GTF-2H5/TTDA is a non-essential transcription factor indispensable for DNA repair

C. elegansTFIIH subunit GTF-2H5/TTDA is a non-essential transcription factor indispensable for DNA repair

The XPB Subunit of the TFIIH Complex Plays a Critical Role in HIV-1 Transcription, and XPB Inhibition by Spironolactone Prevents HIV-1 Reactivation from Latency

Growth factor-loaded ovarian extracellular matrix hydrogels promote in vivo ovarian niche regeneration and enhance fertility in premature ovarian insufficiency preclinical models

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