Is TFIIH the new Achilles heel of cancer cells?

Berico, Pietro; Coin, Frédéric

doi:10.1080/21541264.2017.1331723

Cited by 16 publications

(7 citation statements)

References 31 publications

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“…Several inhibitors of XPB and Cdk7 have been developed to curb transcription addiction in cancer cells and pinpoint these activities as potential targets in cancer chemotherapy [44]. Among them, spironolactone acts distinctively by inducing specific degradation of XPB via the ubiquitin-proteasome system.…”

Section: Discussionmentioning

confidence: 99%

Spironolactone-induced XPB degradation requires TFIIH integrity and ubiquitin-selective segregase VCP/p97

Chauhan

Sun

et al. 2020

Cell Cycle

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Section: Discussionmentioning

confidence: 99%

Spironolactone-induced XPB degradation requires TFIIH integrity and ubiquitin-selective segregase VCP/p97

Chauhan

Sun

et al. 2020

Cell Cycle

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“…Mutations in TFIIH subunits that cause the inherited autosomal recessive disorders xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne syndrome (CS) are characterized by high incidence of cancer or premature ageing ( Cleaver et al, 1999 ; Rapin, 2013 ). Furthermore, TFIIH is a possible target for anti-cancer compounds ( Berico and Coin, 2018 ) and therefore of great importance for human health and disease.…”

Section: Introductionmentioning

confidence: 99%

The complete structure of the human TFIIH core complex

Greber

Toso

Fang

et al. 2019

eLife

100

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Transcription factor IIH (TFIIH) is a heterodecameric protein complex critical for transcription initiation by RNA polymerase II and nucleotide excision DNA repair. The TFIIH core complex is sufficient for its repair functions and harbors the XPB and XPD DNA-dependent ATPase/helicase subunits, which are affected by human disease mutations. Transcription initiation additionally requires the CdK activating kinase subcomplex. Previous structural work has provided only partial insight into the architecture of TFIIH and its interactions within transcription pre-initiation complexes. Here, we present the complete structure of the human TFIIH core complex, determined by phase-plate cryo-electron microscopy at 3.7 Å resolution. The structure uncovers the molecular basis of TFIIH assembly, revealing how the recruitment of XPB by p52 depends on a pseudo-symmetric dimer of homologous domains in these two proteins. The structure also suggests a function for p62 in the regulation of XPD, and allows the mapping of previously unresolved human disease mutations.

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“…A component of the PIC and an interesting target to affect transcription—and therefore cancer—is TFIIH [ 8 , 9 ]. TFIIH is a complex of 10 subunits composed of the CAK subcomplex containing CDK7, CYCH and MAT1, which also participates in cell cycle control, and the core subcomplex that is part of the mechanism of nucleotide excision repair (NER) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Disruption of TFIIH activities generates a stress gene expression response and reveals possible new targets against cancer

et al. 2020

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Disruption of the enzymatic activities of the transcription factor TFIIH by the small molecules Triptolide (TPL) or THZ1 could be used against cancer. Here, we used the MCF10A-ErSrc oncogenesis model to compare the effect of TFIIH inhibitors between transformed cells and their progenitors. We report that tumour cells exhibited highly increased sensitivity to TPL or THZ1 and that the combination of both had a synergic effect. TPL affects the interaction between XPB and p52, causing a reduction in the levels of XPB, p52 and p8, but not other TFIIH subunits. RNA-Seq and RNAPII-ChIP-Seq experiments showed that although the levels of many transcripts were reduced, the levels of a significant number were increased after TPL treatment, with maintained or increased RNAPII promoter occupancy. A significant number of these genes encode for factors that have been related to tumour growth and metastasis, suggesting that transformed cells might rapidly develop resistance to TPL/THZ inhibitors. Some of these genes were also overexpressed in response to THZ1, of which depletion enhances the toxicity of TPL, and are possible new targets against cancer.

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Is TFIIH the new Achilles heel of cancer cells?

Cited by 16 publications

References 31 publications

Spironolactone-induced XPB degradation requires TFIIH integrity and ubiquitin-selective segregase VCP/p97

Spironolactone-induced XPB degradation requires TFIIH integrity and ubiquitin-selective segregase VCP/p97

The complete structure of the human TFIIH core complex

Disruption of TFIIH activities generates a stress gene expression response and reveals possible new targets against cancer

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