Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To understand the role of the various components of TFIIH, a DNA repair/transcription factor, a yeast four-hybrid system was designed. When the ternary Cdk-activating kinase (CAK) complex composed of Cdk7, cyclin H, and MAT1 was used as bait, the xeroderma pigmentosum (XP) D helicase of transcription factor IIH (TFIIH), among other proteins, was identified as an interacting partner. Deletion mutant analyses demonstrated that the coiled-coil and the hydrophobic domains of MAT1 interlink the CAK complex directly with the N-terminal domain of XPD. Using immunoprecipitates from cells coinfected with baculoviruses, we further validated the bridging function of XPD, which anchors CAK to the core TFIIH. In addition we show that upon interaction with MAT1, CAK inhibits the helicase activity of XPD. This inhibition is overcome upon binding to p44, a subunit of the core TFIIH. It is not surprising that under these conditions some XPD mutations affect interactions not only with p44, but also with MAT1, thus preventing either the CAK inhibitory function within CAK.XPD and/or the role of CAK within TFIIH and, consequently, explaining the variety of the XP phenotypes.
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PMID:A yeast four-hybrid system identifies Cdk-activating kinase as a regulator of the XPD helicase, a subunit of transcription factor IIH. 1144 87

The UV-sensitive V-H1 cell line has a T46I substitution mutation in the Walker A box in both alleles of XPD and lacks DNA helicase activity. We characterized three partial revertants that curiously display intermediate UV cytotoxicity (2- to 2.5-fold) but normal levels of UV-induced hprt mutations. In revertant RH1-26, the efficient removal of pyrimidine (6-4) pyrimidone photoproducts from both strands of hprt suggests that global-genomic nucleotide excision repair is normal, but the pattern of cyclobutane pyrimidine dimer removal suggests that transcription-coupled repair (TCR) is impaired. To explain the intermediate UV survival and lack of RNA synthesis recovery in RH1-26 after 10 J of UV/m(2), we propose a defect in repair-transcription coupling, i.e., the inability of the cells to resume or reinitiate transcription after the first TCR event within a transcript. All three revertants carry an R658H suppressor mutation, in one allele of revertants RH1-26 and RH1-53 and in both alleles of revertant RH1-3. Remarkably, the R658H mutation produces the clinical phenotype of trichothiodystrophy (TTD) in several patients who display intermediate UV sensitivity. The XPD(R658H) TTD protein, like XPD(T46I/R658H), is codominant when overexpressed in V-H1 cells and partially complements their UV sensitivity. Thus, the suppressing R658H substitution must restore helicase activity to the inactive XPD(T46I) protein. Based on current knowledge of helicase structure, the intragenic reversion mutation may partially compensate for the T46I mutation by perturbing the XPD structure in a way that counteracts the effect of this mutation. These findings have implications for understanding the differences between xeroderma pigmentosum and TTD and illustrate the value of suppressor genetics for studying helicase structure-function relationships.
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PMID:Restoration of nucleotide excision repair in a helicase-deficient XPD mutant from intragenic suppression by a trichothiodystrophy mutation. 1158 17

DNA helicases are a highly conserved group of enzymes that unwind DNA. They function in all processes in which access to single-stranded DNA is required, including DNA replication, DNA repair and recombination, and transcription of RNA. Defects in helicases functioning in one or more of these processes can result in characteristic human genetic disorders in which genomic instability and predisposition to cancer are common features. So far, different helicase genes have been found mutated in six such disorders. Mutations in XPB and XPD can result in xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy. Mutations in the RecQ-like genes BLM, WRN, and RECQL4 can result in Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome, respectively. Because XPB and XPD function in both nucleotide excision repair and transcription initiation, the cellular phenotypes associated with a deficiency of each one of them include failure to repair mutagenic DNA lesions and defects in the recovery of RNA transcription after UV irradiation. The functions of the RecQ-like genes are unknown; however, a growing body of evidence points to a function in restarting DNA replication after the replication fork has become stalled. The genomic instability associated with mutations in the RecQ-like genes includes spontaneous chromosome instability and elevated mutation rates. Mouse models for nearly all of these entities have been developed, and these should help explain the widely different clinical features that are associated with helicase mutations.
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PMID:DNA helicases, genomic instability, and human genetic disease. 1170 36

The transcription factor TFIIH is involved in both basal transcription and DNA repair. Mutations in the XPD helicase component of TFIIH can result in the diverse clinical features associated with xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). It is generally believed that the multi-system abnormalities associated with TTD are the result of a subtle deficiency in basal transcription. However, to date, there has been no clear demonstration of a defect in expression of any specific gene in individuals with these syndromes. Here we show that the specific mutations in XPD that cause TTD result in reduced expression of the beta-globin genes in these individuals. Eleven TTD patients with characterized mutations in the XPD gene have the haematological features of beta-thalassaemia trait, and reduced levels of beta-globin synthesis and beta-globin mRNA. All these parameters were normal in three patients with XP. These findings provide the first evidence for reduced expression of a specific gene in TTD. They support the hypothesis that many of the clinical features of TTD result from inadequate expression of a diverse set of highly expressed genes.
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PMID:Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy. 1173 44

Proteins having DNA helicase activity play very important roles in many processes involving DNA workings such as replication, repair, and recombination. In this decade, many DNA helicase genes have been cloned as the causative genes of human recessive heredity diseases. These are the causative genes for Xeroderma pigmentosum (XPB and XPD), Cockayne syndrome (CSB), diffuse collagen disease (Ku80), alpha-thalassmia (ATR-X), Bloom syndrome (BLM), Werner syndrome (WRN) and Rothmund-Thomson syndrome (RTS). The yeast homologue genes of these human DNA helicase genes exist. S. cerevisiae RAD25/SSL2, RAD3, RAD26, YKU80/HDF2 and RAD54 are the homologue for XPB/ERCC3, XPD/ERCC2, CSB/ERCC6, Ku80/XRCC5 and ATR-X/HX2, respectively. E coli. recQ gene and S. cerevisiae SGS1 are the homologue for all BLM, WRN and RTS. A search of whole genome of S. cerevisiae revealed that SGS1 is the sole homologue of recQ in S. cerevisiae. Thus it seems likely that SGS1 is a functional homologue of one or several human RecQ family genes. Many basic or essential functions are well conserved in the cells from lower eukaryotic to higher mammalian. The functional analysis in yeast could make an useful insight for the human homologue. To clarify the functions of S. cerevisiae Sgs1 and to get an insight into the functions of Blm, Wrn and Rts, in this study, we analyzed the phenotype of sgs1 disruptant and in detail the cause of the poor sporulation phenotype of sgs1 disruptants in relation to meiotic processes including meiotic recombination. The poor sporulation of sgs1 disruptants was complemented with a mutated SGS1 gene encoding a protein lacking DNA helicase activity; however, the mutated gene could suppress neither the sensitivity of sgs1 disruptants to methyl methanesulfonate (MMS) and hydroxyurea nor the mitotic hyperrecombination phenotype of sgs1 disruptants. The N-terminal 1-45 amino acid region and 698-1195 amino acid region of Sgs1, which including helicase domain and C-terminal RecQ conserved region with helicase activity, were required for complementation of MMS sensitivity and suppression of hyperrecombination of sgs1 disruptants in mitotic growth. The 126-400 and 596-1195 amino acid regions of Sgs1 were required for complementation of poor sporulation and of reduced meiotic functions. These regions required for the mitotic or meiotic functions of Sgs1 were well overlapped with the interaction regions of Top3 and Top2. Some of these results might explain the mechanism of the symptom of RecQ-related syndromes.
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PMID:[Functional analysis of yeast homologue gene associated with human DNA helicase causative syndromes]. 1263 84

Mutations in the XPD gene result in xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), the phenotypes of which are often intricate. To understand the genotype/phenotype relationship, we engineered recombinant TFIIHs in which XPD subunits carry amino acid changes found in XPD patients. We demonstrate that all the XPD mutations are detrimental for XPD helicase activity, thus explaining the NER defect. We also show that TFIIH from TTD patients, but not from XP patients, exhibits a significant in vitro basal transcription defect in addition to a reduced intracellular concentration. Moreover, when XPD mutations prevent interaction with the p44 subunit of TFIIH, transactivation directed by certain nuclear receptors is inhibited, regardless of TTD versus XP phenotype, thus explaining the overlapping symptoms. The implications of these mutations are discussed using a structural model of the XPD protein. Our study provides explanations for the nature and the severity of the various clinical features.
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PMID:Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients. 1282 Sep 75

Nucleotide excision repair (NER) removes damage from DNA in a tightly regulated multiprotein process. The xeroderma pigmentosum group B (XPB) helicase subunit of TFIIH functions in NER and transcription. The serine 751 (S751) residue of XPB was found to be phosphorylated in vivo. This phosphorylation inhibits NER and the microinjection of a phosphomimicking XPB-S751E mutant is unable to correct the NER defect of XP-B cells. Conversely, XPB-S751 dephosphorylation or its substitution with alanine (S751A) restores NER both in vivo and in vitro. Surprisingly, phospho/dephosphorylation of S751 spares TFIIH-dependent transcription. Finally, the phosphorylation of XPB-S751 does not impair the TFIIH unwinding of the DNA around the lesion, but rather prevents the 5' incision triggered by the ERCC1-XPF endonuclease. These data support an additional role for XPB in promoting the incision of the damaged fragment and reveal a point of NER regulation on TFIIH without interference in its transcription activity.
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PMID:Phosphorylation of XPB helicase regulates TFIIH nucleotide excision repair activity. 1554 33

The nucleotide excision repair (NER) is one of the major human DNA repair pathways. Defects in one of the proteins that act in this system result in three distinct autosomal recessive syndromes: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). TFIIH is a nine-protein complex essential for NER activity, initiation of RNA polymerase II transcription and with a possible role in cell cycle regulation. XPD is part of the TFIIH complex and has a helicase function, unwinding the DNA in the 5' --> 3' direction. Mutations in the XPD gene are found in XP, TTD and XP/CS patients, the latter exhibiting both XP and CS symptoms. Correction of DNA repair defects of these cells by transducing the complementing wild-type gene is one potential strategy for helping these patients. Over the last years, adenovirus vectors have been largely used in gene delivering because of their efficient transduction, high titer, and stability. In this work, we present the construction of a recombinant adenovirus carrying the XPD gene, which is coexpressed with the EGFP reporter gene by an IRES sequence, making it easier to follow cell infection. Infection by this recombinant adenovirus grants full correction of SV40-transformed and primary skin fibroblasts obtained from XP-D, TTD and XP/CS patients.
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PMID:Restoring DNA repair capacity of cells from three distinct diseases by XPD gene-recombinant adenovirus. 1565 Jul 64

Mutation of the XPB gene in humans gives rise to the distinct, autosomal recessive disorder, with a striking clinical heterogeneity: xeroderma pigmentosum associated with Cockayne's syndrome and trichothiodystrophy. XPB is a subunit of a multifunctional RNA polymerase II general initiation factor TFIIH and codes for 3'-->5' DNA helicase essential for both nucleotide excision repair (NER) and transcription. Since XPB defective human disease is extremely rare, Chinese hamster ovary (CHO) mutant cell lines belonging to the 3rd rodent complementation group (the hamster ERCC3 gene is the homologue of the human XPB gene) are a unique resource for analyzing structure-function relationships in the ERCC3/XPB protein. We have amplified, cloned and sequenced the ERCC3 genes from wild type and 27-1, UV24 and MMC-2 CHO mutant cell lines and identified the sites of the respective mutations. 27-1 mutant has an A1075G transition (K359E) located at the very beginning of the Ia helicase domain which causes deficiency in open complex formation and in 3', 5' and dual incisions during NER. UV24 cell line has two mutations. First, it is a T1144C transition (S382P) located behind the Ia helicase domain in a region responsible for ERCC3 binding to XPG, p62 and p44. Second mutation is identical with a mutation in MMC-2 mutant. It is a C2215T transition (Q739STOP) causing the truncation of the C-terminus of the protein, responsible for the 5' incision, by 44 amino acids. All mutant cell lines are unable to recover RNA synthesis after 10Jm(-2) UV, suggesting a defect in transcription-coupled repair. Their limited global NER capacity measured by a single-cell gel electrophoresis assay (0.25Jm(-2)) varies from 6% to 11%.
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PMID:Characterization of ERCC3 mutations in the Chinese hamster ovary 27-1, UV24 and MMC-2 cell lines. 1614 48

The severe xeroderma pigmentosum/Cockayne syndrome (XP/CS) syndrome is caused by mutations in the XPB, XPD and XPG genes that encode the helicase subunits of TFIIH and the 3' endonuclease of nucleotide excision repair (NER). Because XPB and XPD have been implicated in p53-mediated apoptosis, we examined the possible involvement of XPG in this process. After ultraviolet light (UV) irradiation, primary fibroblasts of XP complementation group G (XP-G) individuals with CS enter apoptosis more readily than other NER-deficient cells, but this is unlinked to unrepaired damage. These XP-G/CS cells accumulate p53 post-UV but they fail to accumulate the 90/92 kDa isoforms of Mdm2 and their cellular distribution of Mdm2 is impaired. Apoptosis levels revert to wild type, Mdm2 90/92 kDa isoforms accumulate, and Mdm2 regains its normal post-UV nuclear location in transduced XP-G/CS cells expressing wild-type XPG, but not an XPG catalytic site mutant. These results suggest that XPG suppresses UV-induced apoptosis and that this suppression, most simply, requires its endonuclease function.
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PMID:Suppression of UV-induced apoptosis by the human DNA repair protein XPG. 1616 68


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