Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

In addition to xeroderma pigmentosum, mutations in the human XPG gene cause early onset Cockayne syndrome (CS). Here, we provide evidence for the involvement of RAD2, the S. cerevisiae counterpart of XPG, in promoting efficient RNA polymerase II transcription. Inactivation of RAD26, the S. cerevisiae counterpart of the human CSB gene, also causes a deficiency in transcription, and a synergistic decline in transcription occurs in the absence of both the RAD2 and RAD26 genes. Growth is also retarded in the rad2 Delta and rad26 Delta single mutant strains, and a very severe growth inhibition is seen in the rad2 Delta rad26 Delta double mutant. From these and other observations presented here, we suggest that transcriptional defects are the underlying cause of CS.
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PMID:Requirement of yeast RAD2, a homolog of human XPG gene, for efficient RNA polymerase II transcription. implications for Cockayne syndrome. 1211 Jan 80

We investigated the association of urinary bladder cancer with genetic polymorphisms in the xeroderma pigmentosum complementation group C (XPC), group D (XPD) and group G (XPG), X-ray repair cross-complementing group 1 (XRCC1) and group 3 (XRCC3), Nijmegen breakage syndrome 1 (NBS1), cyclin D1, methylene-tetrahydrofolate reductase (MTHFR), NAD(P)H dehydrogenase quinone 1 (NQO1), H-ras and glutathione S-transferase theta 1 (GSTT1) genes. Bladder cancer patients from the different hospitals in Stockholm County Council area and matching controls were genotyped for different polymorphisms. The frequency of the variant allele for A/C polymorphism in exon 15 of the XPC gene was significantly higher in the bladder cancer cases than in the controls (OR 1.49, 95% CI 1.16-1.92, P = 0.001). The variant allele homozygote genotype for the T/C polymorphism in exon 1 of the H-ras gene was associated with a decreased risk for bladder cancer (OR 0.12, 95% CI 0.02-0.67, P = 0.006). The variant allele genotypes for the single nucleotide polymorphisms (SNPs) in DNA repair genes, XPG and NBS1, showed a marginal association with the occurrence of bladder cancer (OR 0.38, 95% CI 0.15-0.94, P = 0.03 and OR 1.64, 95% CI 0.92-2.90, P = 0.09, respectively). We also report a positive correlation between the null homozygote of GSTT1 with the risk of bladder cancer (OR 2.54, 95% CI 1.32-4.98, P = 0.003). For other polymorphisms included in this study, NBS1 Glu185Gln, XPD Lys751Gln, XPG Asp1104His, XRCC1 Arg399Gln, XRCC3 Thr241Met, cyclin D1 Pro242Pro, MTHFR Ala222Val and Glu429Ala, NQO1 Arg139Trp and Pro187Ser, no significant differences for genotype distributions and allele frequencies between the bladder cancer cases and the controls were observed in the present study.
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PMID:Polymorphisms in DNA repair and metabolic genes in bladder cancer. 1468 16

Xeroderma pigmentosum (XP) is an autosomal recessive disease characterized by sun sensitivity, early onset of freckling and subsequent neoplastic changes on sun-exposed skin. Skin abnormalities result from an inability to repair UV-damaged DNA because of defects in the nucleotide excision repair (NER) machinery. Xeroderma pigmentosum is genetically heterogeneous and is classified into seven complementation groups (XPA-XPG) that correspond to genetic alterations in one of seven genes involved in NER. The variant type of XP (XPV), first described in 1970 by Ernst G. Jung as 'pigmented xerodermoid', is caused by defects in the post replication repair machinery while NER is not impaired. Identification of the XPV gene was only achieved in 1999 by biochemical purification and sequencing of a protein from HeLa cell extracts complementing the PRR defect in XPV cells. The XPV protein, polymerase (pol)eta, represents a novel member of the Y family of bypass DNA polymerases that facilitate DNA translesion synthesis. The major function of (pol)eta is to allow DNA translesion synthesis of UV-induced TT-dimers in an error-free manner; it also possesses the capability to bypass other DNA lesions in an error-prone manner. Xeroderma pigmentosum V is caused by molecular alterations in the POLH gene, located on chromosome 6p21.1-6p12. Affected individuals are homozygous or compound heterozygous for a spectrum of genetic lesions, including nonsense mutations, deletions or insertions, confirming the autosomal recessive nature of the condition. Identification of POLH as the XPV gene provides an important instrument for improving molecular diagnostics in XPV families.
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PMID:Molecular genetics of Xeroderma pigmentosum variant. 1470 92

I provide a personal account of the discovery, cloning and functional analyses of the human XPG gene. Mutations in this gene can give rise to the group G form of xeroderma pigmentosum (XP) and, in some cases, to severe early onset Cockayne syndrome (CS). The XPG protein has well established catalytic and structural roles in nucleotide excision repair (NER) and it acts as a cofactor for a DNA glycosylase that removes oxidised pyrimidines from DNA. XPG may also be involved in transcription-coupled repair of this kind of damage, in transcription by RNA polymerase II, and perhaps in other processes too. Our current knowledge of this important protein is largely based on some excellent, highly focussed science. But good luck, serendipity and scientific scandal have also made major contributions to this unfinished story.
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PMID:The XPG story. 1472 17

Xeroderma pigmentosum (XP) is a human genetic disease which is caused by defects in nucleotide excision repair. Since this repair pathway is responsible for removing UV irradiation-induced damage to DNA, XP patients are hypersensitive to sunlight and are prone to develop skin cancer. Based on the underlying genetic defect, the disease can be divided into the seven complementation groups XPA through XPG. XPF, in association with ERCC1, constitutes a structure-specific endonuclease that makes an incision 5' to the photodamage. XPF-ERCC1 has also been implicated in both removal of interstrand DNA cross-links and homology-mediated recombination and in immunoglobulin class switch recombination (CSR). To study the function of XPF in vivo, we inactivated the XPF gene in mice. XPF-deficient mice showed a severe postnatal growth defect and died approximately 3 weeks after birth. Histological examination revealed that the liver of mutant animals contained abnormal cells with enlarged nuclei. Furthermore, embryonic fibroblasts defective in XPF are hypersensitive to UV irradiation and mitomycin C treatment. No defect in CSR was detected, suggesting that the nuclease is dispensable for this recombination process. These phenotypes are identical to those exhibited by the ERCC1-deficient mice, consistent with the functional association of the two proteins. The complex phenotype suggests that XPF-ERCC1 is involved in multiple DNA repair processes.
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PMID:Growth retardation, early death, and DNA repair defects in mice deficient for the nucleotide excision repair enzyme XPF. 1472 65

In addition to xeroderma pigmentosum (XP), mutations in the human XPG gene cause early onset of Cockayne syndrome (CS) in some patients (XPG/CS). The CS-causing mutations in such patients all produce truncated XPG proteins. To test the hypothesis that the CS phenotype, with characteristics such as growth retardation and a short life span in XPG/CS patients, results from C-terminal truncations, we constructed mutants with C-terminal truncations in mouse XPG (Xpg) (from residue D811 to the stop codon [XpgD811stop] and deletion of exon 15 [Xpg Delta ex15]). In the XpgD811stop and Xpg Delta ex15 mutations, the last 360 and 183 amino acids of the protein were deleted, respectively. To generate Xpg mutant mice, we devised the shortcut knock-in method by replacing genomic DNA with a mutated cDNA fragment (cDNA-mediated knock in). The control mice, in which one-half of Xpg genomic DNA fragment was replaced with a normal Xpg cDNA fragment, had a normal growth rate, a normal life span, normal sensitivity to UV light, and normal DNA repair ability, indicating that the Xpg gene partially replaced with the normal cDNA fragment retained normal functions. The XpgD811stop homozygous mice exhibited growth retardation and a short life span, but the Xpg Delta ex15 homozygous mice did not, indicating that deletion of the last 360 amino acids results in the CS phenotype but deletion of the last 183 amino acids does not. The XpgD811stop homozygous mice, however, exhibited a slightly milder CS phenotype than did the Xpg null mutant mice, indicating that the XpgD811stop protein still retains some Xpg function that affects the severity of the CS phenotype.
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PMID:Identification of the XPG region that causes the onset of Cockayne syndrome by using Xpg mutant mice generated by the cDNA-mediated knock-in method. 1508 67

Xeroderma pigmentosum (XP) patients exhibit a 1000-fold increased risk for developing skin cancers including malignant melanoma. We investigated the role of three variant alleles of the DNA repair gene XPC and one variant allele of the XPG gene in a hospital-based case-control study of 294 Caucasian patients from Germany with malignant melanoma and 375 healthy control individuals from the same area matched by sex. The polymorphisms G1580A (XPC exon 8; Arg492His), T1601C (XPC exon 8; Val499Ala), G2166A (XPC exon 10; Arg687Arg), and C3507G (XPG exon 15; Asp1104His) were not in linkage disequilibrium. The allele frequencies (cases: controls) were for 1580A 6.29%: 5.63%, for 1601C 79.08%: 78.28%, for 2166A 26.19%: 28.13%, and for 3507G 79.86%: 78.61%. We found no association of the homozygous 1580A, 1601C, 2166A, and 3507G genotypes with increased risks of melanoma: OR 1.254 (95% CI: 0.486-3.217), OR 1.108 (95% CI: 0.629-1.960), OR 0.817 (95% CI: 0.490-1.358), and OR 1.168 (95% CI: 0.670-2.044), respectively. Exploratory analyses of subgroups of melanoma patients compared to all controls indicated no association of these genotypes with increased risks for development of multiple primary melanomas (n = 28), a negative family history for melanoma (n = 277), melanomas in individuals with a low number of nevi (n = 273), melanomas in individuals older than 55 years (n = 142), and melanomas thicker than 1 mm (n = 126).
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PMID:No association between three xeroderma pigmentosum group C and one group G gene polymorphisms and risk of cutaneous melanoma. 1549 39

XPG is the human endonuclease that cuts 3' to DNA lesions during nucleotide excision repair. Missense mutations in XPG can lead to xeroderma pigmentosum (XP), whereas truncated or unstable XPG proteins cause Cockayne syndrome (CS), normally yielding life spans of <7 years. One XP-G individual who had advanced XP/CS symptoms at 28 years has been identified. The genetic, biochemical, and cellular defects in this remarkable case provide insight into the onset of XP and CS, and they reveal a previously unrecognized property of XPG. Both of this individual's XPG alleles produce a severely truncated protein, but an infrequent alternative splice generates an XPG protein lacking seven internal amino acids, which can account for his very slight cellular UV resistance. Deletion of XPG amino acids 225 to 231 does not abolish structure-specific endonuclease activity. Instead, this region is essential for interaction with TFIIH and for the stable recruitment of XPG to sites of local UV damage after the prior recruitment of TFIIH. These results define a new functional domain of XPG, and they demonstrate that recruitment of DNA repair proteins to sites of damage does not necessarily lead to productive repair reactions. This observation has potential implications that extend beyond nucleotide excision repair.
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PMID:Definition of a short region of XPG necessary for TFIIH interaction and stable recruitment to sites of UV damage. 1557 72

In addition to xeroderma pigmentosum (XP), mutations in the human XPG gene cause an early onset of Cockayne syndrome (CS) in some patients (XP-G/CS) with characteristics, such as growth retardation and a short life span. In the previous studies, we generated four Xpg mutant mice with two different C-terminal truncations, null, or a base substitution mutation to identify the protein region that causes the onset of CS, and found that the CS-causing mutations, null or a deletion of the last 360 amino acids, completely inhibited the NER activity of mouse XPG (Xpg), but the non-CS-causing mutations, XpgD811A (base substitution that eliminates the nuclease activity of Xpg) or XpgDeltaex15 (deletion of the exon 15 corresponding to the last 183 amino acids), resulted in the retention of residual NER activity. To understand why mutations that completely eliminate the NER activity of Xpg cause CS but those that abolish the nuclease activity without totally eliminating the NER activity of Xpg do not result in CS, we made a series of Xpg mutant mice with Xpa-null mutant allele and found that mice with the non-CS-causing deletion mutation (XpgDeltaex15) exhibited the CS phenotype when XPA was also absent but the base substitution mutation (XpgD811A) that eliminated the Xpg nuclease activity did not. These results indicate that Xpg has a second function, beside NER, and that the disruption of this second function (deletion of the last 183 amino acids) when combined with an NER defect causes CS. When we compared amino acid sequences corresponding to the exon 15 of Xpg, a significant homology was conserved among vertebrates, but not in Drosophila and Saccharomyces cerevisiae. These observations suggest that the second function of XPG may be conserved only in vertebrates and CS symptoms may occur in its absence.
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PMID:Severe growth retardation and short life span of double-mutant mice lacking Xpa and exon 15 of Xpg. 1566 58

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


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