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Jean Marc Egly - One of the best experts on this subject based on the ideXlab platform.
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Trichothiodystrophy view from the molecular basis of dna repair transcription factor tfiih
Human Molecular Genetics, 2009Co-Authors: Satoru Hashimoto, Jean Marc EglyAbstract:Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by brittle hair and also associated with various systemic symptoms. Approximately half of TTD patients exhibit photosensitivity, resulting from the defect in the nucleotide excision repair. Photosensitive TTD is due to mutations in three genes encoding XPB, XPD and p8/TTDA subunits of the DNA repair/transcription factor TFIIH. Mutations in these subunits disturb either the catalytic and/or the regulatory activity of the two XPB, XPD helicase/ ATPases and consequently are defective in both, DNA repair and transcription. Moreover, mutations in any of these three TFIIH subunits also disturb the overall architecture of the TFIIH complex and its ability to trans-activate certain nuclear receptor-responsive genes, explaining in part, some of the TTD phenotypes.
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Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH
Human molecular genetics, 2009Co-Authors: Satoru Hashimoto, Jean Marc EglyAbstract:Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by brittle hair and also associated with various systemic symptoms. Approximately half of TTD patients exhibit photosensitivity, resulting from the defect in the nucleotide excision repair. Photosensitive TTD is due to mutations in three genes encoding XPB, XPD and p8/TTDA subunits of the DNA repair/transcription factor TFIIH. Mutations in these subunits disturb either the catalytic and/or the regulatory activity of the two XPB, XPD helicase/ ATPases and consequently are defective in both, DNA repair and transcription. Moreover, mutations in any of these three TFIIH subunits also disturb the overall architecture of the TFIIH complex and its ability to trans-activate certain nuclear receptor-responsive genes, explaining in part, some of the TTD phenotypes.
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Structural basis for group A Trichothiodystrophy
Nature structural & molecular biology, 2008Co-Authors: Denis E. Kainov, Marc Vitorino, Jean Cavarelli, Arnaud Poterszman, Jean Marc EglyAbstract:Patients with the rare neurodevelopmental repair syndrome known as group A Trichothiodystrophy (TTD-A) carry mutations in the gene encoding the p8 subunit of the transcription and DNA repair factor TFIIH. Here we describe the crystal structure of a minimal complex between Tfb5, the yeast ortholog of p8, and the C-terminal domain of Tfb2, the yeast p52 subunit of TFIIH. The structure revealed that these two polypeptides adopt the same fold, forming a compact pseudosymmetric heterodimer via a beta-strand addition and coiled coils interactions between terminal alpha-helices. Furthermore, Tfb5 protects a hydrophobic surface in Tfb2 from solvent, providing a rationale for the influence of p8 in the stabilization of p52 and explaining why mutations that weaken p8-p52 interactions lead to a reduced intracellular TFIIH concentration and a defect in nucleotide-excision repair, a common feature of TTD cells.
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Trichothiodystrophy, a transcription syndrome
Trends in genetics : TIG, 2001Co-Authors: Etienne Bergmann, Jean Marc EglyAbstract:Trichothiodystrophy (TTD) is a rare genetic disorder characterized by a hair dysplasia and associated with numerous symptoms affecting mainly organs derived from the neuroectoderm. About half of TTD patients exhibit photosensitivity because their nucleotide-excision repair pathway (NER) does not remove UV-induced DNA lesions efficiently. However, they do not present the skin cancer susceptibility expected from such an NER disorder. Their deficiencies result from phenotype-specific mutations in either XPB or XPD. These genes encode the helicase subunits of TFIIH, a DNA repair factor that is also required for transcription of class II genes. Thus, time- and tissue-specific impairments of transcription might explain the developmental and neurological symptoms of TTD. In a third group of photosensitive patients, TTD-A, no mutation has been identified, although TFIIH amount is reduced.
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sublimiting concentration of tfiih transcription dna repair factor causes ttd a Trichothiodystrophy disorder
Nature Genetics, 2000Co-Authors: Wim Vermeulen, Etienne Bergmann, Jérôme Auriol, Suzanne Rademakers, Philippe Frit, Esther Appeldoorn, Jan H.j. Hoeijmakers, Jean Marc EglyAbstract:The repair-deficient form of Trichothiodystrophy (TTD) most often results from mutations in the genes XPB or XPD, encoding helicases of the transcription/repair factor TFIIH. The genetic defect in a third group, TTD-A, is unknown, but is also caused by dysfunctioning TFIIH. None of the TFIIH subunits carry a mutation and TFIIH from TTD-A cells is active in both transcription and repair. Instead, immunoblot and immunofluorescence analyses reveal a strong reduction in the TFIIH concentration. Thus, the phenotype of TTD-A appears to result from sublimiting amounts of TFIIH, probably due to a mutation in a gene determining the complex stability. The reduction of TFIIH mainly affects its repair function and hardly influences transcription.
Alan R Lehmann - One of the best experts on this subject based on the ideXlab platform.
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Transcriptional changes in Trichothiodystrophy cells
DNA repair, 2008Co-Authors: Judith Offman, Nipurna Jina, Therina Theron, Jacky Pallas, Mike Hubank, Alan R LehmannAbstract:Mutations in three of the genes encoding the XPB, XPD and TTDA components of transcription factor TFIIH can result in the clinical phenotype of Trichothiodystrophy (TTD). Different mutations in XPB and XPD can instead cause xeroderma pigmentosum (XP). The completely different features of these disorders have been attributed to TTD being a transcription syndrome. In order to detect transcriptional differences between TTD and XP cells from the XP-D complementation group, we have compared gene expression profiles in cultured fibroblasts from normal, XP and TTD donors. Although we detected transcriptional differences between individual cell strains, using an algorithm of moderate stringency, we did not identify any genes whose expression was reproducibly different in proliferating fibroblasts from each type of donor. Following UV-irradiation, many genes were up- and down-regulated in all three cell types. The microarray analysis indicated some apparent differences between the different donor types, but on more detailed inspection, these turned out to be false positives. We conclude that there are minimal differences in gene expression in proliferating fibroblasts from TTD, XP-D and normal donors.
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dna repair deficient diseases xeroderma pigmentosum cockayne syndrome and Trichothiodystrophy
Biochimie, 2003Co-Authors: Alan R LehmannAbstract:Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and Trichothiodystrophy (TTD) are genetic disorders with very different clinical features, but all associated with defects in nucleotide excision repair. Defects in the XPA or XPC genes confer sensitivity to UV carcinogenesis in both humans and mice, but only XPA?/? mice have increased acute responses to UV exposure, whereas XPC?/? mice are normal in this respect. Both XPE and XPF proteins have functions separate from their role in NER, but the exact nature of these functions has not yet been established. The CSA and CSB genes responsible for CS are both components of complexes associated with RNA polymerase II and their role is thought to be in assisting polII in dealing with transcription blocks. XPB and XPD proteins are components of transcription factor TFIIH, which is involved in both basal and activated transcription. XPB is part of the core of TFIIH and has a central role in transcription, whereas XPD connects the core to the CAK subcomplex, and can tolerate many different mutations. Subtle differences in the effects of these different mutations on the many activities of TFIIH and on its stability determine the clinical outcomes, which can be XP, TTD, XP with CS, XP with TTD or COFS. Features of single and double mutant mice indicate that the neurological and ageing features associated with these disorders result from the defects in NER in association with the transcriptional deficiencies. Skin tumours in XP patients have mutations characteristic of UV-induction in the ras, p53 and ptch genes, showing that sunlight-induced mutations in these genes are important in carcinogenesis in XP patients.
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mutations in the xeroderma pigmentosum group d dna repair transcription gene in patients with Trichothiodystrophy
Nature Genetics, 1994Co-Authors: Bernard C. Broughton, Christine A Weber, H. Steingrimsdottir, Alan R LehmannAbstract: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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Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with Trichothiodystrophy
Nature genetics, 1994Co-Authors: Bernard C. Broughton, Christine A Weber, H. Steingrimsdottir, Alan R LehmannAbstract: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.
James E. Cleaver - One of the best experts on this subject based on the ideXlab platform.
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cancer in xeroderma pigmentosum and related disorders of dna repair
Nature Reviews Cancer, 2005Co-Authors: James E. CleaverAbstract:Nucleotide-excision repair diseases exhibit cancer, complex developmental disorders and neurodegeneration. Cancer is the hallmark of xeroderma pigmentosum (XP), and neurodegeneration and developmental disorders are the hallmarks of Cockayne syndrome and Trichothiodystrophy. A distinguishing feature is that the DNA- repair or DNA-replication deficiencies of XP involve most of the genome, whereas the defects in CS are confined to actively transcribed genes. Many of the proteins involved in repair are also components of dynamic multiprotein complexes, transcription factors, ubiquitylation cofactors and signal-transduction networks. Complex clinical phenotypes might therefore result from unanticipated effects on other genes and proteins.
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Splitting hairs--discovery of a new DNA repair and transcription factor for the human disease Trichothiodystrophy.
DNA repair, 2005Co-Authors: James E. CleaverAbstract:The gene responsible for the TTD-A group of the DNA repair deficient disease Trichothiodystrophy has been identified as a small, 8 kDa, component of the transcription factor TFIIH which contributes to the stability and concentration of TFIIH in vivo.
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a summary of mutations in the uv sensitive disorders xeroderma pigmentosum cockayne syndrome and Trichothiodystrophy
Human Mutation, 1999Co-Authors: James E. Cleaver, Larry H Thompson, Audrey S Richardson, Christopher J StatesAbstract:The human diseases xeroderma pigmentosum, Cockayne syndrome, and Trichothiodystrophy are caused by mutations in a set of interacting gene products, which carry out the process of nucleotide excision repair. The majority of the genes have now been cloned and many mutations in the genes identified. The relationships between the distribution of mutations in the genes and the clinical presentations can be used for diagnosis and for understanding the functions and the modes of interaction among the gene products. The summary presented here represents currently known mutations that can be used as the basis for future studies of the structure, function, and biochemical properties of the proteins involved in this set of complex disorders, and may allow determination of the critical sites for mutations leading to different clinical manifestations. The summary indicates where more data are needed for some complementation groups that have few reported mutations, and for the groups for which the gene(s) are not yet cloned. These include the Xeroderma pigmentosum (XP) variant, the Trichothiodystrophy group A (TTDA), and ultraviolet sensitive syndrome (UVs) groups. We also recommend that the XP-group E should be defined explicitly through molecular terms, because assignment by complementation in culture has been difficult. XP-E by this definition contains only those cell lines and patients that have mutations in the small subunit, DDB2, of a damage-specific DNA binding protein. Hum Mutat 14:9–22, 1999. © 1999 Wiley-Liss, Inc.
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dna repair characteristics and mutations in the ercc2 dna repair and transcription gene in a Trichothiodystrophy patient
Human Mutation, 1997Co-Authors: Kyoko Takayama, James E. Cleaver, David M Danks, Edmund P Salazar, Christine A WeberAbstract:Patient TTD183ME is male and has typical Trichothiodystrophy characteristics, including brittle hair, ichthyosis, characteristic face with receding chin and protruding ears, sun sensitivity, and mental and growth retardation. The relative amount of NER carried out by a TTD183ME fibroblast cell strain after ultraviolet (UV) exposure was ∼65% of normal as determined by a method that converts repair patches into quantifiable DNA breaks. UV survival curves show a reduction in survival only at doses greater than 4 J/m2. Nucleotide sequence analysis of the ERCC2 (XPD) DNA repair and transcription gene cDNA revealed both a Leu461-to-Val substitution and a deletion of amino acids 716–730 in one allele and an Ala725-to-Pro substitution in the other allele. The first allele has also been reported in one xeroderma pigmentosum group D patient and two other Trichothiodystrophy patients, while the second allele has not been previously reported. Comparisons suggest that the mutation of Ala725 to Pro correlates with TTD with intermediate UV sensitivity. Hum Mutat 9:519–525, 1997. © 1997 Wiley-Liss, Inc.
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DNA repair characteristics and mutations in the ERCC2 DNA repair and transcription gene in a Trichothiodystrophy patient
Human mutation, 1997Co-Authors: Kyoko Takayama, James E. Cleaver, David M Danks, Edmund P Salazar, Christine A WeberAbstract:Patient TTD183ME is male and has typical Trichothiodystrophy characteristics, including brittle hair, ichthyosis, characteristic face with receding chin and protruding ears, sun sensitivity, and mental and growth retardation. The relative amount of NER carried out by a TTD183ME fibroblast cell strain after ultraviolet (UV) exposure was ∼65% of normal as determined by a method that converts repair patches into quantifiable DNA breaks. UV survival curves show a reduction in survival only at doses greater than 4 J/m2. Nucleotide sequence analysis of the ERCC2 (XPD) DNA repair and transcription gene cDNA revealed both a Leu461-to-Val substitution and a deletion of amino acids 716–730 in one allele and an Ala725-to-Pro substitution in the other allele. The first allele has also been reported in one xeroderma pigmentosum group D patient and two other Trichothiodystrophy patients, while the second allele has not been previously reported. Comparisons suggest that the mutation of Ala725 to Pro correlates with TTD with intermediate UV sensitivity. Hum Mutat 9:519–525, 1997. © 1997 Wiley-Liss, Inc.
Christine A Weber - One of the best experts on this subject based on the ideXlab platform.
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dna repair characteristics and mutations in the ercc2 dna repair and transcription gene in a Trichothiodystrophy patient
Human Mutation, 1997Co-Authors: Kyoko Takayama, James E. Cleaver, David M Danks, Edmund P Salazar, Christine A WeberAbstract:Patient TTD183ME is male and has typical Trichothiodystrophy characteristics, including brittle hair, ichthyosis, characteristic face with receding chin and protruding ears, sun sensitivity, and mental and growth retardation. The relative amount of NER carried out by a TTD183ME fibroblast cell strain after ultraviolet (UV) exposure was ∼65% of normal as determined by a method that converts repair patches into quantifiable DNA breaks. UV survival curves show a reduction in survival only at doses greater than 4 J/m2. Nucleotide sequence analysis of the ERCC2 (XPD) DNA repair and transcription gene cDNA revealed both a Leu461-to-Val substitution and a deletion of amino acids 716–730 in one allele and an Ala725-to-Pro substitution in the other allele. The first allele has also been reported in one xeroderma pigmentosum group D patient and two other Trichothiodystrophy patients, while the second allele has not been previously reported. Comparisons suggest that the mutation of Ala725 to Pro correlates with TTD with intermediate UV sensitivity. Hum Mutat 9:519–525, 1997. © 1997 Wiley-Liss, Inc.
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DNA repair characteristics and mutations in the ERCC2 DNA repair and transcription gene in a Trichothiodystrophy patient
Human mutation, 1997Co-Authors: Kyoko Takayama, James E. Cleaver, David M Danks, Edmund P Salazar, Christine A WeberAbstract:Patient TTD183ME is male and has typical Trichothiodystrophy characteristics, including brittle hair, ichthyosis, characteristic face with receding chin and protruding ears, sun sensitivity, and mental and growth retardation. The relative amount of NER carried out by a TTD183ME fibroblast cell strain after ultraviolet (UV) exposure was ∼65% of normal as determined by a method that converts repair patches into quantifiable DNA breaks. UV survival curves show a reduction in survival only at doses greater than 4 J/m2. Nucleotide sequence analysis of the ERCC2 (XPD) DNA repair and transcription gene cDNA revealed both a Leu461-to-Val substitution and a deletion of amino acids 716–730 in one allele and an Ala725-to-Pro substitution in the other allele. The first allele has also been reported in one xeroderma pigmentosum group D patient and two other Trichothiodystrophy patients, while the second allele has not been previously reported. Comparisons suggest that the mutation of Ala725 to Pro correlates with TTD with intermediate UV sensitivity. Hum Mutat 9:519–525, 1997. © 1997 Wiley-Liss, Inc.
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mutations in the xeroderma pigmentosum group d dna repair transcription gene in patients with Trichothiodystrophy
Nature Genetics, 1994Co-Authors: Bernard C. Broughton, Christine A Weber, H. Steingrimsdottir, Alan R LehmannAbstract: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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Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with Trichothiodystrophy
Nature genetics, 1994Co-Authors: Bernard C. Broughton, Christine A Weber, H. Steingrimsdottir, Alan R LehmannAbstract: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.
Etienne Bergmann - One of the best experts on this subject based on the ideXlab platform.
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Trichothiodystrophy, a transcription syndrome
Trends in genetics : TIG, 2001Co-Authors: Etienne Bergmann, Jean Marc EglyAbstract:Trichothiodystrophy (TTD) is a rare genetic disorder characterized by a hair dysplasia and associated with numerous symptoms affecting mainly organs derived from the neuroectoderm. About half of TTD patients exhibit photosensitivity because their nucleotide-excision repair pathway (NER) does not remove UV-induced DNA lesions efficiently. However, they do not present the skin cancer susceptibility expected from such an NER disorder. Their deficiencies result from phenotype-specific mutations in either XPB or XPD. These genes encode the helicase subunits of TFIIH, a DNA repair factor that is also required for transcription of class II genes. Thus, time- and tissue-specific impairments of transcription might explain the developmental and neurological symptoms of TTD. In a third group of photosensitive patients, TTD-A, no mutation has been identified, although TFIIH amount is reduced.
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sublimiting concentration of tfiih transcription dna repair factor causes ttd a Trichothiodystrophy disorder
Nature Genetics, 2000Co-Authors: Wim Vermeulen, Etienne Bergmann, Jérôme Auriol, Suzanne Rademakers, Philippe Frit, Esther Appeldoorn, Jan H.j. Hoeijmakers, Jean Marc EglyAbstract:The repair-deficient form of Trichothiodystrophy (TTD) most often results from mutations in the genes XPB or XPD, encoding helicases of the transcription/repair factor TFIIH. The genetic defect in a third group, TTD-A, is unknown, but is also caused by dysfunctioning TFIIH. None of the TFIIH subunits carry a mutation and TFIIH from TTD-A cells is active in both transcription and repair. Instead, immunoblot and immunofluorescence analyses reveal a strong reduction in the TFIIH concentration. Thus, the phenotype of TTD-A appears to result from sublimiting amounts of TFIIH, probably due to a mutation in a gene determining the complex stability. The reduction of TFIIH mainly affects its repair function and hardly influences transcription.
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Sublimiting concentration of TFIIH transcription/DNA repair factor causes TTD-A Trichothiodystrophy disorder.
Nature genetics, 2000Co-Authors: Wim Vermeulen, Etienne Bergmann, Jérôme Auriol, Suzanne Rademakers, Philippe Frit, Esther Appeldoorn, Jan H.j. Hoeijmakers, Jean Marc EglyAbstract:The repair-deficient form of Trichothiodystrophy (TTD) most often results from mutations in the genes XPB or XPD, encoding helicases of the transcription/repair factor TFIIH. The genetic defect in a third group, TTD-A, is unknown, but is also caused by dysfunctioning TFIIH. None of the TFIIH subunits carry a mutation and TFIIH from TTD-A cells is active in both transcription and repair. Instead, immunoblot and immunofluorescence analyses reveal a strong reduction in the TFIIH concentration. Thus, the phenotype of TTD-A appears to result from sublimiting amounts of TFIIH, probably due to a mutation in a gene determining the complex stability. The reduction of TFIIH mainly affects its repair function and hardly influences transcription.
