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

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

PROVIDER: PRJNA558076 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9884530.fastq.gz	Fastqsanger.gz
	SRR9884531.fastq.gz	Fastqsanger.gz
	SRR9884522.fastq.gz	Fastqsanger.gz
	SRR9884532.fastq.gz	Fastqsanger.gz
	SRR9884523.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

Project description:The global effect on transcription between cancer cells and their progenitors and investigating how these compounds affect TFIIH integrity. Here, we used an oncogenesis model to compare the effect of TFIIH inhibitors: TPL and THZ1 between transformed cells and their progenitors. 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

2020-07-08 | GSE135256 | GEO

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

Project description: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.

| S-EPMC7333893 | biostudies-literature

TFIIH mutants treated with methyl methanesulfonate

Project description:Purpose of profiling experiment was to examine effects of a mutation of a subunit of TFIIH, ssl1p, which has ubiquitin ligase activity. The whole complex has previously been shown to have both kinase and helicase activities. We wanted to see if 1) there were general transcriptional defects with these mutations, as there are with other mutations to kinase activity, and 2) if there were transcriptional effects on DNA repair machinery when the mutants were treated with MMS, which is an alkylating agent. Keywords: other

2005-04-20 | GSE2343 | GEO

Transcription profiling of S. cerevisiae TFIIH mutants treated with methyl methanesulfonate

Project description:Purpose of profiling experiment was to examine effects of a mutation of a subunit of TFIIH, ssl1p, which has ubiquitin ligase activity.,The whole complex has previously been shown to have both kinase and helicase activities. We wanted to see if 1) there were,general transcriptional defects with these mutations, as there are with other mutations to kinase activity, and 2) if there,were transcriptional effects on DNA repair machinery when the mutants were treated with MMS, which is an alkylating agent.

2007-07-08 | E-GEOD-2343 | biostudies-arrayexpress

Structural basis of TFIIH activation for nucleotide excision repair

Project description:Nucleotide excision repair (NER) is the major DNA repair pathway that removes UV-induced and bulky DNA lesions. There is currently no structure of NER intermediates, which form around the large multisubunit transcription factor IIH (TFIIH). Here we report the cryo-EM structure of an NER intermediate containing TFIIH and the NER factor XPA. Compared to its transcription conformation, the TFIIH structure is rearranged such that its ATPase subunits XPB and XPD bind double- and single-stranded DNA, consistent with their translocase and helicase activities, respectively. XPA releases the inhibitory kinase module of TFIIH, displaces a ‘plug’ element from the DNA-binding pore in XPD, and together with the NER factor XPG stimulates XPD activity. Our results explain how TFIIH is switched from a transcription to a repair factor, and provide the basis for a mechanistic analysis of the NER pathway.

2019-07-02 | PXD013947 | Pride

Systematic mutagenesis identifies p52/Tfb2 residues required for XPB/Ssl2 function within TFIIH and genetic interactions with TFB6

Project description:TFIIH is an evolutionarily conserved complex that plays central roles in both RNA polymerase II (pol II) transcription and DNA repair. As an integral component of the pol II Pre-Initiation Complex, TFIIH regulates the activity of the pol II enzyme in numerous ways. One of the essential functions of TFIIH resides in its XPB/Ssl2 subunit. XPB/Ssl2 is an ATP-dependent DNA translocase that stimulates promoter opening prior to transcription initiation. Crosslinking-mass spectrometry and cryo-EM results have shown a conserved interaction network involving XPB/Ssl2 and the C-terminal Hub region of the p52/Tfb2 core subunit. Here, we systematically mutagenized the HubA region of Tfb2 and screened for growth phenotypes in a TFB6 deletion background in Saccharomyces cerevisiae. We identified six lethal and twelve conditional mutants. Growth phenotypes of all but three of the conditional mutants were suppressed in the presence of Tfb6, thus identifying a functional interaction between Tfb2 HubA mutants and Tfb6, a protein that dissociates Ssl2 from TFIIH. Biochemical analysis of p52/Tfb2 mutants with severe growth phenotypes revealed defects in XPB/Ssl2 association. Further characterization of these Tfb2 mutant cells revealed defects in induction of Gal genes, and reduced occupancy TFIIH and pol II at Gal gene promoters, suggesting that functional TFIIH is required for proper Pol II recruitment to PICs in vivo. Consistent with recent structural models of TFIIH, our results identify key residues in the p52/Tfb2 HubA domain that are required for stable incorporation of XPB/Ssl2 into TFIIH, and for pol II transcription.

2022-06-30 | GSE196069 | GEO

Ssl2/TFIIH Function in Transcription Start Site Scanning by RNA Polymerase II in Saccharomyces cerevisiae

Project description:The initial step of RNA polymerase II (Pol II) transcription involves a large number of transcription factors and arises at multiple sites within most promoters. TFIIH is an essential, multi-subunit transcription factor that assembles on promoter DNA with Pol II and five other general transcription factors (GTFs) to form a pre-initiation complex (PIC) for basal transcription. During transcription initiation, TFIIH melts promoter DNA through the ATPase activity of its Ssl2 subunit. In the model eukaryote Saccharomyces cerevisiae, after DNA melting, Pol II scans downstream for usable transcription start sites (TSSs). To understand the function of Ssl2/TFIIH in promoter scanning and TSS selection, we identified novel alleles of SSL2 in genetic screens for mutants defective in TSS distribution that may potentially arise from altered scanning. Consistent with this notion, these ssl2 alleles alter scanning in ways that are distinct from how changes to the Pol II active site alter scanning and this difference is observed genome-wide. Our investigations support two major pathways in controlling promoter scanning and TSS selection, one controlling the efficiency of initiation through Pol II activity or factors regulating Pol II activity; another network appears to control the processivity of scanning by Ssl2/TFIIH.

2021-08-28 | GSE182792 | GEO

Genome binding profile of TFIIH helicases XPB and XPD in HT1080 cells

Project description:The conserved TFIIH helicases XPB and XPD play key roles in transcription initiation and DNA repair. To investigate the functions of these helicases on a genome-wide scale, we performed ChIP-seq of endogenous XPB and XPD in the HT1080 human fibrosarcoma cell line. 2 ChIP samples and 1 unenriched input control from the same crosslinked chromatin pool

2014-02-18 | E-GEOD-44849 | biostudies-arrayexpress

Genome binding profile of TFIIH helicases XPB and XPD in HT1080 cells

2014-02-18 | GSE44849 | GEO

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

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

2021-11-19 | PXD029008 | Pride

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