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)

DNA repair defects in the xeroderma pigmentosum (XP) group D complementation group can be associated with the clinical features of two quite different disorders; XP, a sun-sensitive and cancer-prone disorder, or trichothiodystrophy (TTD) which is characterized by sulphur-deficient brittle hair and a variety of other associated abnormalities, but no skin cancer. The XPD gene product, a DNA helicase, is required for nucleotide excision repair and recent evidence has demonstrated a role in transcription. We have now identified causative mutations in XPD in four TTD patients. The patients are all compound heterozygotes and the locations of the mutations enable us to suggest relationships between different domains in the gene and its roles in excision repair and transcription.
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PMID:Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy. 792 Jun 40

Trichothiodystrophy (TTD), an autosomal recessive disorder characterized by sulfur-deficient brittle hair, identifies a group of genetic disorders with an altered synthesis of high-sulfur matrix proteins and a defect in excision repair of ultraviolet damage in fibroblasts of most TTD patients. In contrast to patients with xeroderma pigmentosum (XP), TTD patients do not have an increased frequency of skin cancers. TTD patients may be grouped into four categories: 1) those without photosensitivity and without a defect in excision repair of UV damage; 2) those without photosensitivity and with an excision-repair defect in the same gene as in XP-D (complementation group D); 3) those with photosensitivity and with the XP-D repair defect; 4) those with photosensitivity and with a repair defect distinct from that in XP-D. We present a brother and sister in the third category of TTD. Clinically, the patients have brittle hair, short stature, ichthyosis, photosensitivity, nail and dental dysplasias, cataracts, mental retardation, and pyramidal tract abnormalities. Diagnosis was made by hair mount, which shows the characteristic banding pattern with polarizing microscopy, and by hair amino acid analysis, which demonstrated decreased high-sulfur matrix proteins. Fibroblasts cultured from skin biopsies had a marked DNA excision repair defect similar to the repair defect seen in XP-D. We have documented a unique dysmyelinating disorder on magnetic resonance imaging of the brain that might explain their mental retardation, marked hyperactivity, and neurologic deficits. Following the discovery that the human excision repair cross complementing rodent ultraviolet group 2 (ERCC2) gene is able to correct the ultraviolet sensitivity of XP-D cell strains, the ERCC2 cDNA from previous TTD patients was sequenced and shows frameshifts, deletions and point mutations in the ERCC2 gene. Molecular analysis of our patients is in progress. Molecular analysis of the defects in ERCC2 in clinically distinct patients with XP,XP/Cockayne's syndrome, and TTD may provide insight into the molecular mechanisms of these genetically related but clinically distinct disorders.
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PMID:Trichothiodystrophy: clinical spectrum, central nervous system imaging, and biochemical characterization of two siblings. 796 80

The cDNA sequence of the Chinese hamster xeroderma pigmentosum group D (CXPD) nucleotide excision repair gene was analyzed from three Chinese hamster ovary (CHO) cell lines: repair proficient strain AA8 and repair deficient, UV complementation group 2 strains UV5 and UVL-13. CXPD encodes a presumed ATP-dependent DNA helicase and is single copy in CHO lines due to the hemizygosity of chromosome 9. Comparison of the deduced wild-type AA8 CXPD protein sequence with that of the Chinese hamster V79 lung-derived cell line revealed two amino acid polymorphisms. Position 285 is glutamine in AA8 and arginine in V79, and position 298 is alanine in AA8 and threonine in V79. Comparison with the human XPD, Saccharomyces cerevisiae RAD3, and Schizosaccharomyces pombe rad15 homologs shows variability at these positions. Analysis of the CXPD sequence in the repair deficient CHO lines UV5 and UVL-13 revealed, in each case, a single base substitution resulting in an amino acid substitution. Position 116 is tyrosine in UV5 and cysteine in AA8, and the corresponding positions of XPD, RAD3, and rad15 are cysteine. Position 615 is glutamic acid in UVL-13 and glycine in AA8, and the corresponding positions of XPD, RAD3, and rad15 are glycine. In both UV5 and UVL-13, positions 285 and 298 are glutamine and alanine, respectively, as seen in AA8. These results suggest that cysteine 116 and glycine 615 are critical to the repair function of CXPD.
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PMID:Molecular analysis of CXPD mutations in the repair-deficient hamster mutants UV5 and UVL-13. 759 68

Trichothiodystrophy (TTD) is a rare genetic disease with heterogeneous clinical features associated with specific deficiencies in nucleotide excision repair. Patients have brittle hair due to a reduced content of cysteine-rich matrix proteins. About 50% of the cases reported in the literature are photosensitive. In these patients an altered cellular response to UV, due to a specific deficiency in nucleotide excision repair, has been observed. The majority of repair-defective TTD patients have been assigned by complementation analysis to group D of xeroderma pigmentosum (XP). Recently, the human excision repair gene ERCC2 has been shown to correct the UV sensitivity of XP-D fibroblasts. In this work we describe the effect of ERCC2 on the DNA repair deficient phenotype of XP-D and on two repair-defective TTD cell strains (TTD1VI and TTD2VI) assigned by complementation analysis to group D of XP. ERCC2 cDNA, cloned into a mammalian expression vector, was introduced into TTD and XP fibroblasts via DNA-mediated transfection or microneedle injection. UV sensitivity and cellular DNA repair properties, including unscheduled DNA synthesis and reactivation of a UV-irradiated plasmid containing the chloramphenicol acetyltransferase reporter gene (pRSVCat), were corrected to wild-type levels in both TTD and XP-D cells. These data show that a functional ERCC2 gene is sufficient to reestablish a wild-type DNA repair phenotype in TTD1VI and TTD2VI cells, confirming the genetic relationship between TTD and XP-D. Furthermore, our findings suggest that mutations at the ERCC2 locus are responsible for causing a similar phenotype in TTD and XP-D cells in response to UV irradiation, but produce quite different clinical symptoms.
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PMID:Correction by the ERCC2 gene of UV sensitivity and repair deficiency phenotype in a subset of trichothiodystrophy cells. 805 25

Because of defective nucleotide excision repair of ultraviolet damaged DNA, xeroderma pigmentosum (XP) patients suffer from a high incidence of skin cancers. Cell fusion studies have identified seven XP complementation groups, A to G. Previous studies have implicated the products of these seven XP genes in the recognition of ultraviolet-induced DNA damage and in incision of the damage-containing DNA strand. Here, we express the XPG-encoded protein in Sf9 insect cells and purify it to homogeneity. We demonstrate that XPG is a single-strand specific DNA endonuclease, thus identifying the catalytic role of the protein in nucleotide excision repair. We suggest that XPG nuclease acts on the single-stranded region created as a result of the combined action of the XPB helicase and XPD helicase at the DNA damage site.
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PMID:Human xeroderma pigmentosum group G gene encodes a DNA endonuclease. 807 65

The RAD3 gene of Saccharomyces cerevisiae is required for excision repair of ultraviolet-damaged DNA and is essential for cell viability. The RAD3-encoded protein shares a high degree of homology with the human ERCC2(XPD) gene product. Mutations in XPD, besides causing the cancer-prone syndrome xeroderma pigmentosum, can also result in Cockayne's syndrome and trichothiodystrophy. To investigate the role of RAD3 in viability, we examined here the effect of a recessive, temperature-sensitive (ts) conditional lethal mutation of the gene on transcription by RNA polymerase II. Upon transfer to the restrictive temperature, the rad3-ts mutant rapidly ceases growth and poly(A)+ RNA synthesis is inhibited drastically. Messenger RNA levels of all the genes examined, HIS3, TRP3, STE2, MET19, RAD23, CDC7, CDC9 and ACT1, decline rapidly upon loss of RAD3 activity. The synthesis of heat-shock-inducible HSP26 mRNA and galactose-inducible GAL7 and GAL10 mRNAs is also drastically inhibited in the rad3-ts mutant at the restrictive temperature. The RNA polymerase II transcriptional activity in extract from the rad3-ts14 strain is thermolabile, and this in vitro transcriptional defect can be fully corrected by the addition of homogeneous RAD3 protein. These findings indicate that RAD3 protein has a direct and essential role in RNA polymerase II transcription.
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PMID:DNA repair gene RAD3 of S. cerevisiae is essential for transcription by RNA polymerase II. 810 80

Nucleotide-excision repair (NER) is an important cellular defence mechanism against mutagenesis and carcinogenesis. The essential yeast genes RAD3 (ref. 2) and SSL2 (RAD25), homologues of the human xeroderma pigmentosum genes XPD and XPB respectively, have been implicated in NER in yeast. The products of these genes are also subunits of (Rad3 protein) or associate with (Ssl2 protein) purified yeast RNA polymerase II transcription initiation factor b, the counterpart of human TFIIH. Rad3 and Ssl2 proteins may participate directly in NER. Alternatively, they may function exclusively as transcription factors that support NER by influencing the expression of other NER genes. Here we show that defective NER in rad3 mutant extracts can be specifically complemented by purified transcription factor b. Similarly, defective NER in ssl2 mutant extracts is corrected by purified factor b/Ssl2 complex. These results support a direct role of factor b during NER in yeast. Hence, factor b (TFIIH) has a dual role in transcription and NER.
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PMID:Transcription factor b (TFIIH) is required during nucleotide-excision repair in yeast. 810 88

The RAD3 gene of Saccharomyces cerevisiae is required for excision repair of UV-damaged DNA and is essential for cell viability. Remarkable homology exists between RAD3 and the human excision repair gene XPD, whose mutational inactivation underlies the cancer-prone disorder in xeroderma pigmentosum group D patients. Our previous work demonstrated that RAD3-encoded protein contains a DNA helicase activity. Here, we show that RAD3 binds preferentially to UV-damaged DNA over nondamaged DNA. Removal of pyrimidine dimers from damaged DNA by enzymatic photoreactivation does not affect binding, suggesting an affinity of RAD3 for pyrimidine (6-4) pyrimidone photoproducts. Damage-specific binding by RAD3 is strongly dependent on ATP and on the degree of negative superhelicity in DNA. The requirement of superhelicity in damage binding may target RAD3 to regions of DNA undergoing transcription, resulting in the preferential repair of these regions. The rad3 Arg-48 mutant protein, which lacks the DNA helicase activity, also binds UV-damaged DNA preferentially, indicating that DNA helicase and damage binding are two distinct and separable functional entities in RAD3.
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PMID:Negative superhelicity promotes ATP-dependent binding of yeast RAD3 protein to ultraviolet-damaged DNA. 813 53

The RNA polymerase II general transcription factor TFIIH is composed of several polypeptides. The observation that the largest subunit of TFIIH is the excision-repair protein XPB/ERCC3 (ref. 1), a helicase implicated in the human DNA-repair disorders xeroderma pigmentosum (XP) and Cockayne's syndrome, suggests a functional link between transcription and DNA repair. To understand the connection between these two cellular processes, we have extensively purified and functionally analysed TFIIH. We find that TFIIH has a dual role, being required for basal transcription of class II genes and for participation in DNA-excision repair. TFIIH is shown to complement three different cell extracts deficient in excision repair: XPB/ERCC3, XPC and XPD/ERCC2. The complementation of XPB and XPD is a consequence of ERCC3 and ERCC2 being integral subunits of TFIIH, whereas complementation of XPC is due to an association of this polypeptide with TFIIH. We found that the general transcription factor IIE negatively modulates the helicase activity of TFIIH through a direct interaction between TFIIE and the ERCC3 subunit of TFIIH.
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PMID:Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II. 815 90

The sun-sensitive, cancer-prone genetic disorder xeroderma pigmentosum (XP) is associated in most cases with a defect in the ability to carry out excision repair of UV damage. Seven genetically distinct complementation groups (i.e., A-G) have been identified. A large proportion of patients with the unrelated disorder trichothiodystrophy (TTD), which is characterized by hair-shaft abnormalities, as well as by physical and mental retardation, are also deficient in excision repair of UV damage. In most of these cases the repair deficiency is in the same complementation group as is XP group D. We report here on cells from a patient, TTD1BR, in which the repair defect complements all known XP groups (including XP-D). Furthermore, microinjection of various cloned human repair genes fails to correct the repair defect in this cell strain. The defect in TTD1BR cells is therefore in a new gene involved in excision repair in human cells. The finding of a second DNA repair gene that is associated with the clinical features of TTD argues strongly for an involvement of repair proteins in hair-shaft development.
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PMID:A new nucleotide-excision-repair gene associated with the disorder trichothiodystrophy. 821 12


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