Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sun-sensitive form of the severe neurodevelopmental, brittle hair disorder trichothiodystrophy (TTD) is caused by point mutations in the essential XPB and XPD helicase subunits of the dual functional DNA repair/basal transcription factor TFIIH. The phenotype is hypothesized to be in part derived from a nucleotide excision repair defect and in part from a subtle basal transcription deficiency accounting for the nonrepair TTD features. Using a novel gene-targeting strategy, we have mimicked the causative XPD point mutation of a TTD patient in the mouse. TTD mice reflect to a remarkable extent the human disorder, including brittle hair, developmental abnormalities, reduced life span, UV sensitivity, and skin abnormalities. The cutaneous symptoms are associated with reduced transcription of a skin-specific gene strongly supporting the concept of TTD as a human disease due to inborn defects in basal transcription and DNA repair.
Mol Cell 1998 Jun
PMID:A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy. 965 81

To understand the initiation of the transcription of protein-coding genes, we have dissected the role of the basal transcription/DNA repair factor TFIIH. Having succeeded in reconstituting a functionally active TFIIH from baculovirus recombinant polypeptides, we were able to analyze the role of XPB, XPD, and cdk7 subunits in the transcription reaction. Designing mutated recombinant subunits, we show that the XPB helicase is absolutely required for transcription to open the promoter around the start site whereas the XPD helicase, which is dispensable, stimulates transcription and allows the CAK complex to be anchored to TFIIH. In addition, we also show that cdk7 may phosphorylate the carboxy-terminal domain (CTD) of RNA pol II in the absence of promoter opening.
Mol Cell 1999 Jan
PMID:Reconstitution of the transcription factor TFIIH: assignment of functions for the three enzymatic subunits, XPB, XPD, and cdk7. 1002 82

The human XPB DNA helicase is a subunit of the DNA repair/basal transcription factor TFIIH, involved in early steps of the nucleotide excision repair pathway. Two distinct clinical phenotypes, xeroderma pigmentosum associated with Cockayne's syndrome (XP/CS) and trichothiodystrophy (TTD), can be due to mutations in the XPB gene. In the present work, we studied cellular DNA repair properties of skin fibro-blasts from two patients mutated in the XPB gene: an XP/CS patient cell (XPCS2BA) with a T296C (F99S) transition and a TTD patient cell (TTD6VI) exhibiting an A355C (T119P) transversion. Both cells are clearly associated with different levels of alterations in their response to UV light. To establish the relationship between the relative expression level of these two alleles and DNA repair properties, we transfected SV40-transformed XPCS2BA (XPCS2BASV) cells with a plasmid (pTTD6VI) carrying the XPB-A355C cDNA and examined DNA repair properties after UV irradiation (cell survival, unscheduled DNA synthesis and kinetics of photoproduct removal) in stable transfectants. We isolated three clones, which express the XPB-A355C gene (Cl-5) or the XPB-T296C gene (Cl-14) or both genes (Cl-19). This con-stitutes a model system allowing us to correlate the relative expression levels of the XPB-A355C (TTD) and XPB-T296C (XP/CS) genes with various DNA repair properties. Overexpression of the XPB-A355C (TTD) gene in an XP/CS cell gives rise to a cellular phenotype of increased repair similar to that of TTD6VI cells, while equal expression of the two mutated genes leads to an intermediate cellular phenotype between XP/CS and TTD.
Hum Mol Genet 1999 Jun
PMID:The relative expression of mutated XPB genes results in xeroderma pigmentosum/Cockayne's syndrome or trichothiodystrophy cellular phenotypes. 1033 46

FUSE-binding protein (FBP) binds the single-stranded far upstream element of active c-myc genes, possesses potent transcription activation and repression domains, and is necessary for c-myc expression. A novel 60 kDa protein, the FBP interacting repressor (FIR), blocked activator-dependent, but not basal, transcription through TFIIH. Recruited through FBP's nucleic acid-binding domain, FIR formed a ternary complex with FBP and FUSE. FIR repressed a c-myc reporter via the FUSE. The amino terminus of FIR contained an activator-selective repression domain capable of acting in cis or even in trans in vivo and in vitro. The repression domain of FIR targeted only TFIIH's p89/XPB helicase, required at several stages in transcription, but not factors required for promoter selection. Thus, FIR locks TFIIH in an activation-resistant configuration that still supports basal transcription.
Mol Cell 2000 Feb
PMID:The FBP interacting repressor targets TFIIH to inhibit activated transcription. 1088 74

The mechanisms by which DNA interstrand cross-links (ICLs) are repaired in mammalian cells are unclear. Studies in bacteria and yeasts indicate that both nucleotide excision repair (NER) and recombination are required for their removal and that double-strand breaks are produced as repair intermediates in yeast cells. The role of NER and recombination in the repair of ICLs induced by nitrogen mustard (HN2) was investigated using Chinese hamster ovary mutant cell lines. XPF and ERCC1 mutants (defective in genes required for NER and some types of recombination) and XRCC2 and XRCC3 mutants (defective in RAD51-related homologous recombination genes) were highly sensitive to HN2. Cell lines defective in other genes involved in NER (XPB, XPD, and XPG), together with a mutant defective in nonhomologous end joining (XRCC5), showed only mild sensitivity. In agreement with their extreme sensitivity, the XPF and ERCC1 mutants were defective in the incision or "unhooking" step of ICL repair. In contrast, the other mutants defective in NER activities, the XRCC2 and XRCC3 mutants, and the XRCC5 mutant all showed normal unhooking kinetics. Using pulsed-field gel electrophoresis, DNA double-strand breaks (DSBs) were found to be induced following nitrogen mustard treatment. DSB induction and repair were normal in all the NER mutants, including XPF and ERCC1. The XRCC2, XRCC3, and XRCC5 mutants also showed normal induction kinetics. The XRCC2 and XRCC3 homologous recombination mutants were, however, severely impaired in the repair of DSBs. These results define a role for XPF and ERCC1 in the excision of ICLs, but not in the recombinational components of cross-link repair. In addition, homologous recombination but not nonhomologous end joining appears to play an important role in the repair of DSBs resulting from nitrogen mustard treatment.
Mol Cell Biol 2000 Nov
PMID:Defining the roles of nucleotide excision repair and recombination in the repair of DNA interstrand cross-links in mammalian cells. 1102 68

Mutations in XPB and XPD TFIIH helicases have been related with three hereditary human disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. The dual role of TFIIH in DNA repair and transcription makes it difficult to discern which of the mutant TFIIH phenotypes is due to defects in any of these different processes. We used haywire (hay), the Drosophila XPB homolog, to dissect this problem. Our results show that when hay dosage is affected, the fly shows defects in structures that require high levels of transcription. We found a genetic interaction between hay and cdk7, and we propose that some of these phenotypes are due to transcriptional deficiencies. We also found more apoptotic cells in imaginal discs and in the CNS of hay mutant flies than in wild-type flies. Because this abnormal level of apoptosis was not detected in cdk7 flies, this phenotype could be related to defects in DNA repair. In addition the apoptosis induced by p53 Drosophila homolog (Dmp53) is suppressed in heterozygous hay flies.
Mol Biol Cell 2002 Sep
PMID:DNA repair and transcriptional effects of mutations in TFIIH in Drosophila development. 1222 Nov 29

Trichothiodystrophy (TTD) is a rare hereditary multisystem disorder associated with defects in nucleotide excision repair (NER) as a consequence of mutations in XPD, XPB or TTDA, three genes that are all related to TFIIH, the multiprotein complex involved in NER and transcription. Here we show that all the mutations found in TTD cases, irrespective of whether they are homozygotes, hemizygotes or compound heterozygotes, cause a substantial and specific reduction (by up to 70%) in the cellular concentration of TFIIH. Intriguingly, the degree of reduction in the level of TFIIH does not correlate with the severity of the pathological phenotype, suggesting that the severity of the clinical features in TTD cannot be related solely to the effects of mutations on the stability of TFIIH. We have also measured TFIIH levels in cells in which different mutations in the XPD gene are associated with clinical symptoms not of TTD but of the highly cancer-prone disorder xeroderma pigmentosum (XP). We have found mild reductions (up to 40%) in TFIIH content in some but not all of these cell strains. We conclude that the severity of the clinical features in TTD patients and the clinical outcome of differentially mutated XPD proteins is likely to depend both on the effects that each mutation has on the stability of TFIIH and on the transcriptional activity of the residual TFIIH complexes.
Hum Mol Genet 2002 Nov 01
PMID:Reduced level of the repair/transcription factor TFIIH in trichothiodystrophy. 1239 3

Mutation in the CSB gene results in the human Cockayne's syndrome (CS). Here, we provide evidence that CSB is found not only in the nucleoplasm but also in the nucleolus within a complex (CSB IP/150) that contains RNA pol I, TFIIH, and XPG and promotes efficient rRNA synthesis. CSB is active in in vitro RNA pol I transcription and restores rRNA synthesis when transfected in CSB-deficient cells. We also show that mutations in CSB, as well as in XPB and XPD genes, all of which confer CS, disturb the RNA pol I/TFIIH interaction within the CSB IP/150. In addition to revealing an unanticipated function for CSB in rRNA synthesis, we show that the fragility of this complex could be one factor contributing to the CS phenotype.
Mol Cell 2002 Oct
PMID:CSB is a component of RNA pol I transcription. 1241 26

The fission yeast Schizosaccharomyces pombe is often used as a genetic system to model processes that apply to higher cells. Here S.pombe was used to study promoter DNA opening and transcription initiation by RNA polymerase II. The melted region within the adh promoter is about 20 bp in size and has the start site near its center. This arrangement is similar to that at the AdML promoter but different from that in Saccharomyces cerevisiae. Although expression of human TFIIB shifts the start site to the nearby human position, it does not change the location of the bubble. The start site shift is directed by the C terminus of human TFIIB, in contrast to expectations from S.cerevisiae. The creation of the bubble requires the ATPase motifs of XPB. Overall, the data show that promoter melting and initiation in fission yeast is much more similar to humans than to budding yeast.
J Mol Biol 2004 Jul 23
PMID:The Schizosaccharomyces pombe open promoter bubble: mammalian-like arrangement and properties. 1523 61

Splenic marginal zone lymphoma (SMZL) is a lymphoma type of putative marginal zone B-cell origin. No specific genetic alterations have yet been demonstrated in SMZL. Clinically, SMZL is a low-grade B-cell non-Hodgkin lymphoma. However, the presence of p53 mutation, 7q22-7q32 deletion or the absence of somatic hypermutations of immunoglobulin genes has been correlated with a worse prognosis. In this study, we analyzed genome-wide gene expression of 24 cases of SMZL using the microarray technique. The AP-1 transcription factors c-jun, junD, junB, and c-fos as well as Notch2 were found to be specifically up-regulated. These data were confirmed by real-time PCR and immunohistochemical staining of tissue sections. The absence of concordant high expression of the MAP kinases, the signaling cascade leading to AP-1 up-regulation, suggests autoregulation of the AP-1 transcription factors and an important role in SMZL oncogenesis. High expression of Notch2, a transcription factor that induces marginal zone B-cell differentiation, is highly suggestive for a marginal zone B-cell origin of SMZL. In addition, SMZL with the 7q deletion showed high expression of TGF-beta1 and low expression of the DNA helicase XPB, a crucial part of the nucleotide excision repair complex, possibly explaining the more aggressive clinical course of those cases.
J Mol Diagn 2004 Nov
PMID:Constitutive expression of the AP-1 transcription factors c-jun, junD, junB, and c-fos and the marginal zone B-cell transcription factor Notch2 in splenic marginal zone lymphoma. 1550 68


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