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The Journal of Investigative Dermatology Jan 1990There is evidence for defective DNA repair in xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy, but for increased cancer risk only in xeroderma...
There is evidence for defective DNA repair in xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy, but for increased cancer risk only in xeroderma pigmentosum. Natural and adaptive immune surveillance and mutant frequency to 6-thioguanine resistance in circulating T-lymphocytes were studied in five patients with xeroderma pigmentosum, two with Cockayne's syndrome, and one with trichothiodystrophy. Forty-eight-hour cutaneous hypersensitivity responses to recall antigens excluded anergy and circulating CD3+, CD4+, CD8+, and CD16+ cell numbers were within normal limits in all patients tested, as were proliferative lymphocyte responses to PHA, except in the trichothiodystrophy patient. Proliferative responses to recall antigens (PPD, SKSD, and Candida) showed that all patients responded to one or more antigens. Direct natural killer cytotoxicity measured against the human erythromyeloid leukaemia cell line K562 using a 4-h 51Cr release assay was significantly reduced in xeroderma pigmentosum (specific cytotoxicity less than mean +/- SD greater than 17.4 +/- 9.4 per cent, with effector:target cell ratio of 50:1) compared to normal controls (45.8 +/- 17.8), but normal in Cockayne's syndrome and trichothiodystrophy. Generation of lymphokine activated killer cell activity was normal in the two xeroderma pigmentosum lines tested. The mutant frequency in the xeroderma pigmentosum donors was significantly increased (p less than 0.01) and was elevated in the two Cockayne's syndrome donors, taking age into account. No mutants were observed from the single trichothiodystrophy donor. These findings suggest that reduced natural killer cell activity may contribute to the greatly increased susceptibility to skin cancer in xeroderma pigmentosum.
Topics: Antigens, CD; Cockayne Syndrome; Cytotoxicity, Immunologic; DNA Repair; Dwarfism; Female; Hair Diseases; Humans; Ichthyosis; Immune System; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Lymphocyte Activation; Lymphocytes; Male; Mutation; Neoplasms; Risk Factors; Skin Diseases; Skin Tests; Xeroderma Pigmentosum
PubMed: 2295840
DOI: 10.1111/1523-1747.ep12873952 -
Actas Dermo-sifiliograficas Apr 2007Trichothiodystrophy comprises a heterogeneous group of autosomal recessive entities. This fact gives rise to different interrelated neuroectodermal disorders. From a...
Trichothiodystrophy comprises a heterogeneous group of autosomal recessive entities. This fact gives rise to different interrelated neuroectodermal disorders. From a structural point of view these features are the result of the low tissue sulfur content. We report a case of trichothiodystrophy initially classified as Tay syndrome that based on clinical features, complementary exams as well as on the disease evolution was labelled as PIBIDS syndrome.
Topics: Aging, Premature; DNA Repair; Female; Genes, Recessive; Growth Disorders; Hair; Hair Diseases; Humans; Ichthyosis; Infant; Lentigo; Neurocutaneous Syndromes; Phenotype; Photosensitivity Disorders; Sulfur
PubMed: 17504703
DOI: No ID Found -
Mutation Research Jan 2007Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are... (Review)
Review
Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) are - except for the skin - not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features.
Topics: Animals; Carcinogens; DNA Damage; DNA Repair; Humans; Mice; Models, Genetic; Mutagens; Mutation; Organ Specificity; Phenotype; Xeroderma Pigmentosum
PubMed: 16769089
DOI: 10.1016/j.mrfmmm.2005.12.018 -
Journal of Molecular and Genetic... 2018The S100B protein is an intra- and extracellular signaling protein that plays a role in a multitude of cellular processes and abnormal S100B is associated with various...
The S100B protein is an intra- and extracellular signaling protein that plays a role in a multitude of cellular processes and abnormal S100B is associated with various neurological diseases and cancers. S100B recognizes and binds effector proteins in a calcium-dependent manner. S100B has been shown to interact with the actin capping protein CapZ, protein kinase C, Hdm2 and 4, RAGE receptor, and p, among others. These protein partners interact with a common area on the S100B protein surface, validating the method of using the consensus sequence for S100B target search. In addition, each S100B target protein distinguishes itself by additional contacts with S100B. This perspective suggests that the combination of sequence homology search and structural analysis promises to identify newer S100B-binding partners beyond the use of the consensus sequence alone as the given example in the XPB subunit of the TFIIH general transcription factor. XPB is a helicase required for both transcription and DNA repair. Inherited xpb mutations are associated with human disease Xeroderma Pigmentasum, Cockayne syndrome, and trichothiodystrophy. S100B protein is likely associated with much more biological pathways and processes. We believe that S100B will attract more and more attentions in the scientific community and S100B related studies will have important implications in human health and medicine.
PubMed: 30854023
DOI: 10.4172/1747-0862.1000366 -
Proceedings of the National Academy of... Jun 2021The cancer-free photosensitive trichothiodystrophy (PS-TTD) and the cancer-prone xeroderma pigmentosum (XP) are rare monogenic disorders that can arise from mutations in...
The cancer-free photosensitive trichothiodystrophy (PS-TTD) and the cancer-prone xeroderma pigmentosum (XP) are rare monogenic disorders that can arise from mutations in the same genes, namely or Both XPD and XPB proteins belong to the 10-subunit complex transcription factor IIH (TFIIH) that plays a key role in transcription and nucleotide excision repair, the DNA repair pathway devoted to the removal of ultraviolet-induced DNA lesions. Compelling evidence suggests that mutations affecting the DNA repair activity of TFIIH are responsible for the pathological features of XP, whereas those also impairing transcription give rise to TTD. By adopting a relatives-based whole transcriptome sequencing approach followed by specific gene expression profiling in primary fibroblasts from a large cohort of TTD or XP cases with mutations in gene, we identify the expression alterations specific for TTD primary dermal fibroblasts. While most of these transcription deregulations do not impact on the protein level, very low amounts of prostaglandin I synthase (PTGIS) are found in TTD cells. PTGIS catalyzes the last step of prostaglandin I synthesis, a potent vasodilator and inhibitor of platelet aggregation. Its reduction characterizes all TTD cases so far investigated, both the PS-TTD with mutations in TFIIH coding genes as well as the nonphotosensitive (NPS)-TTD. A severe impairment of TFIIH and RNA polymerase II recruitment on the promoter is found in TTD but not in XP cells. Thus, PTGIS represents a biomarker that combines all PS- and NPS-TTD cases and distinguishes them from XP.
Topics: Animals; Cells, Cultured; Cytochrome P-450 Enzyme System; Epoprostenol; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation; Mice; Neoplasms; Skin; Transcription, Genetic; Trichothiodystrophy Syndromes; Ultraviolet Rays; Xeroderma Pigmentosum
PubMed: 34155103
DOI: 10.1073/pnas.2024502118 -
Clinical and Experimental Dermatology Oct 2021Click here for the corresponding questions to this CME article.
Click here for the corresponding questions to this CME article.
Topics: Antibodies, Monoclonal, Humanized; Child; Humans; Injections, Subcutaneous; Interleukin-4 Receptor alpha Subunit; Male; Receptors, Interleukin-13; Trichothiodystrophy Syndromes
PubMed: 33955026
DOI: 10.1111/ced.14642 -
American Journal of Human Genetics Aug 2019Brittle and "tiger-tail" hair is the diagnostic hallmark of trichothiodystrophy (TTD), a rare recessive disease associated with a wide spectrum of clinical features...
Brittle and "tiger-tail" hair is the diagnostic hallmark of trichothiodystrophy (TTD), a rare recessive disease associated with a wide spectrum of clinical features including ichthyosis, intellectual disability, decreased fertility, and short stature. As a result of premature abrogation of terminal differentiation, the hair is brittle and fragile and contains reduced cysteine content. Hypersensitivity to UV light is found in about half of individuals with TTD; all of these individuals harbor bi-allelic mutations in components of the basal transcription factor TFIIH, and these mutations lead to impaired nucleotide excision repair and basal transcription. Different genes have been found to be associated with non-photosensitive TTD (NPS-TTD); these include MPLKIP (also called TTDN1), GTF2E2 (also called TFIIEβ), and RNF113A. However, a relatively large group of these individuals with NPS-TTD have remained genetically uncharacterized. Here we present the identification of an NPS-TTD-associated gene, threonyl-tRNA synthetase (TARS), found by next-generation sequencing of a group of uncharacterized individuals with NPS-TTD. One individual has compound heterozygous TARS variants, c.826A>G (p.Lys276Glu) and c.1912C>T (p.Arg638), whereas a second individual is homozygous for the TARS variant: c.680T>C (p.Leu227Pro). We showed that these variants have a profound effect on TARS protein stability and enzymatic function. Our results expand the spectrum of genes involved in TTD to include genes implicated in amino acid charging of tRNA, which is required for the last step in gene expression, namely protein translation. We previously proposed that some of the TTD-specific features derive from subtle transcription defects as a consequence of unstable transcription factors. We now extend the definition of TTD from a transcription syndrome to a "gene-expression" syndrome.
Topics: Alleles; Amino Acid Sequence; Case-Control Studies; Hair Diseases; Humans; Mutation; Phenotype; Sequence Homology; Threonine-tRNA Ligase; Transcription Factor TFIIH; Trichothiodystrophy Syndromes
PubMed: 31374204
DOI: 10.1016/j.ajhg.2019.06.017 -
Medecine Sciences : M/S Dec 2006DNA helicases are molecular motors that catalyse the unwinding of energetically unstable structures into single strands and have therefore an essential role in nearly... (Review)
Review
DNA helicases are molecular motors that catalyse the unwinding of energetically unstable structures into single strands and have therefore an essential role in nearly all metabolism transactions. Defects in helicase function can result in human syndromes in which predisposition to cancer and genomic instability are common features. So far different helicase genes have been found associated in 8 such disorders. RecQ helicases are a family of conserved enzymes required for maintaining the genome integrity that function as suppressors of inappropriate recombination. Mutations in RecQ4, BLM and WRN give rise to various disorders: Bloom syndrome, Rothmund-Thomson syndrome, and Werner syndrome characterized by genomic instability and increased cancer susceptibility. The DNA helicase BRIP1/BACH1 is involved in double-strand break repair and is defective in Fanconi anemia complementation group J. Mutations in XPD and XPB genes can result in xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy, three genetic disorders with different clinical features but with association of transcription and NER defects. This review summarizes our current knowledge on the diverse biological functions of these helicases and the molecular basis of the associated diseases.
Topics: Abnormalities, Multiple; DNA Damage; DNA Helicases; DNA Repair; Genetic Diseases, Inborn; Humans; Models, Genetic
PubMed: 17156731
DOI: 10.1051/medsci/200622121087 -
Nature Structural & Molecular Biology Jun 2019Transcription preinitiation complexes (PICs) are vital assemblies whose function underlies the expression of protein-encoding genes. Cryo-EM advances have begun to...
Transcription preinitiation complexes (PICs) are vital assemblies whose function underlies the expression of protein-encoding genes. Cryo-EM advances have begun to uncover their structural organization. Nevertheless, functional analyses are hindered by incompletely modeled regions. Here we integrate all available cryo-EM data to build a practically complete human PIC structural model. This enables simulations that reveal the assembly's global motions, define PIC partitioning into dynamic communities and delineate how structural modules function together to remodel DNA. We identify key TFIIE-p62 interactions that link core-PIC to TFIIH. p62 rigging interlaces p34, p44 and XPD while capping the DNA-binding and ATP-binding sites of XPD. PIC kinks and locks substrate DNA, creating negative supercoiling within the Pol II cleft to facilitate promoter opening. Mapping disease mutations associated with xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome onto defined communities reveals clustering into three mechanistic classes that affect TFIIH helicase functions, protein interactions and interface dynamics.
Topics: Cell Cycle Proteins; DNA; Humans; Models, Molecular; Protein Interaction Maps; Protein Subunits; Transcription Factor TFIIH; Transcription Factors; Transcription Factors, TFII; Transcription Initiation, Genetic
PubMed: 31110295
DOI: 10.1038/s41594-019-0220-3 -
FEBS Letters Jun 2001Once a large proportion of the genes responsible for genetic disorders are identified in the post-genome era, the fundamental challenge is to establish a... (Review)
Review
Once a large proportion of the genes responsible for genetic disorders are identified in the post-genome era, the fundamental challenge is to establish a genotype/phenotype relationship. Our aim is to explain how mutations in a given gene affect its enzymatic function and, in consequence, disturb the life of the cell. Genome integrity is continuously threatened by the occurrence of DNA damage arising from cellular exposure to irradiation and genotoxic chemicals. This mutagenic or potentially lethal DNA damage induces various cellular responses including cell cycle arrest, transcription alteration and processing by DNA repair mechanisms, such as the nucleotide excision repair (NER) pathway. Disruption of NER in response to genotoxic injuries results in autosomal recessive hereditary diseases such as Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). One of the most immediate consequences of the induction of strand-distorting lesions is the arrest of transcription in which TFIIH plays a role in addition to its role in DNA repair. The observations made by clinicians close to XP, TTD and CS patients, suggested that transcription defects responsible for brittle hair and nails for TTD, or developmental abnormalities for CS, resulted from TFIIH mutations. Here a story will be related which could be called 'a multi-faceted factor named TFIIH'. As biochemists, we have characterized each component of TFIIH, three of which are XPB and XPD helicases and cdk7, a cyclin-dependent kinase. With the help of structural biologists, we have characterized most of the specific three-dimensional structures of TFIIH subunits and obtained its electron microscopy image. Together these approaches help us to propose a number of structure-function relationships for TFIIH. Through transfection and microinjection assays, cell biology allows us to determine the role of TFIIH in transcription and NER. We are thus in a position to explain, at least in part, transcription initiation mechanisms and their coupling to DNA repair. We now know how the XPB helicase opens the promoter region for RNA synthesis and that one of the roles of XPD helicase is to anchor the cdk7 kinase to the core-TFIIH. In XP and CS associated patients, we have demonstrated that some XPD mutations prevent an optimal phosphorylation of nuclear receptors by cdk7 with, as a consequence, a drop in the expression of genes sensitive to hormone action. We have thus shown that hormonal responses operate through TFIIH. Careful analysis of each TFIIH subunit also shows how the p44 Ring finger participates in certain promoter escape reactions. We are also able to localize the action of TFIIH in the sequence of events that lead to the elimination of DNA lesions. Thanks to the combination of these different approaches we are obtaining a much clearer picture of the TFIIH complex and its integration into the life of the cell.
Topics: Cell Cycle; DNA Repair; Humans; Models, Biological; RNA, Messenger; Transcription Factor TFIIH; Transcription Factors; Transcription Factors, TFII; Transcription, Genetic; Xeroderma Pigmentosum
PubMed: 11412842
DOI: 10.1016/s0014-5793(01)02458-9