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Trends in Genetics : TIG Jun 1993An intricate network of repair systems safeguards the integrity of genetic material, by eliminating DNA lesions induced by numerous environmental and endogenous... (Comparative Study)
Comparative Study Review
An intricate network of repair systems safeguards the integrity of genetic material, by eliminating DNA lesions induced by numerous environmental and endogenous genotoxic agents. Nucleotide excision repair (NER) is one of the most versatile DNA repair systems. Deficiencies in this process give rise to the classical human DNA repair disorders xeroderma pigmentosum (XP) and Cockayne's syndrome (CS), and to a recently recognized disease called PIBIDS, a photosensitive form of the brittle hair disorder trichothiodystrophy. This is the second of a two-part review on NER. Part I (in the previous issue of TIG) concentrated on the main characteristics of the NER pathway of E. coli and yeast. Part II compares the mammalian and yeast systems, and attempts to integrate current knowledge on the eukaryotic pathway to suggest an outline for the reaction mechanism.
Topics: Animals; Cockayne Syndrome; Cricetinae; DNA Repair; Genes, Fungal; Humans; Mammals; Photosensitivity Disorders; Saccharomyces cerevisiae; Xeroderma Pigmentosum
PubMed: 8337762
DOI: 10.1016/0168-9525(93)90121-w -
International Journal of Molecular... Jan 2020Human mutations in the transcription and nucleotide excision repair (NER) factor TFIIH are linked with three human syndromes: xeroderma pigmentosum (XP),... (Review)
Review
Human mutations in the transcription and nucleotide excision repair (NER) factor TFIIH are linked with three human syndromes: xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and Cockayne syndrome (CS). In particular, different mutations in the XPB, XPD and p8 subunits of TFIIH may cause one or a combination of these syndromes, and some of these mutations are also related to cancer. The participation of TFIIH in NER and transcription makes it difficult to interpret the different manifestations observed in patients, particularly since some of these phenotypes may be related to problems during development. TFIIH is present in all eukaryotic cells, and its functions in transcription and DNA repair are conserved. Therefore, has been a useful model organism for the interpretation of different phenotypes during development as well as the understanding of the dynamics of this complex. Interestingly, phenotypes similar to those observed in humans caused by mutations in the TFIIH subunits are present in mutant flies, allowing the study of TFIIH in different developmental processes. Furthermore, studies performed in of mutations in different subunits of TFIIH that have not been linked to any human diseases, probably because they are more deleterious, have revealed its roles in differentiation and cell death. In this review, different achievements made through studies in the fly to understand the functions of TFIIH during development and its relationship with human diseases are analysed and discussed.
Topics: Animals; Disease; Disease Models, Animal; Drosophila Proteins; Drosophila melanogaster; Humans; Mutation; Transcription Factor TFIIH
PubMed: 31963603
DOI: 10.3390/ijms21020630 -
The Journal of Investigative Dermatology Feb 2015Nucleotide excision repair (NER) is an important DNA repair pathway involved in the removal of a wide array of DNA lesions. The absence or dysfunction of NER results in... (Review)
Review
Nucleotide excision repair (NER) is an important DNA repair pathway involved in the removal of a wide array of DNA lesions. The absence or dysfunction of NER results in the following distinct disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS), cerebro-oculo-facio-skeletal (COFS) syndrome, UV-sensitive syndrome (UVSS), trichothiodystrophy (TTD), or combined syndromes including XP/CS, XP/TTD, CS/TTD, and COFS/TTD. In addition to their well-characterized role in the NER signaling pathway, NER factors also seem to be important in biological processes that are not directly associated with DNA damage responses, including mitochondrial function and redox homeostasis. The potential causative role of these factors in the large clinical spectrum seen in NER diseases is discussed in this review.
Topics: Antioxidants; Cockayne Syndrome; DNA Repair; Energy Metabolism; Humans; Oxidation-Reduction; Photosensitivity Disorders; Trichothiodystrophy Syndromes; Xeroderma Pigmentosum
PubMed: 25296907
DOI: 10.1038/jid.2014.365 -
Experimental Dermatology Aug 2022Hair shafts from three trichothiodystrophy (TTD) patients with mutations in the ERCC2 (XPD) gene were examined by transmission electron microscopy. TTD is a rare,...
Hair shafts from three trichothiodystrophy (TTD) patients with mutations in the ERCC2 (XPD) gene were examined by transmission electron microscopy. TTD is a rare, recessive disorder with mutations in several genes in the DNA repair/transcription pathway, including ERCC2. Unlike previous studies, the hair shafts were examined after relaxation of their structure by partial disulphide bond reduction in the presence of sodium dodecyl sulphate, permitting improved visualization. Compared with hair shafts of normal phenotype, TTD cuticle cells displayed aberrant marginal bands and exocuticle layers. Clusters of cells stained differently (light versus dark) in the cortex of aberrant shafts, and the keratin macrofibrils appeared much shorter in the cytoplasm. Considerable heterogeneity in these properties was evident among samples and even along the length of single hair shafts. The results are consistent with not only a paucity of high sulphur components, such as keratin-associated proteins, but also a profound imbalance in protein content and organization.
Topics: DNA Repair; Hair; Hair Diseases; Humans; Trichothiodystrophy Syndromes; Ultraviolet Rays; Xeroderma Pigmentosum Group D Protein
PubMed: 35615778
DOI: 10.1111/exd.14614 -
Journal of Clinical Medicine Jul 2023Disorders of immunity are poorly recognised in some rare multisystem genetic conditions. We aim to describe syndromic features and immunological defects in children with...
BACKGROUND
Disorders of immunity are poorly recognised in some rare multisystem genetic conditions. We aim to describe syndromic features and immunological defects in children with syndromic primary immunodeficiencies (sPIDs).
METHODS
This is a retrospective descriptive study of children aged 0-18 years with sPIDs under the care of the paediatric immunology service at the Bristol Royal Hospital for Children, United Kingdom, from January 2006 to September 2021.
RESULTS
sPIDs were identified in 36 patients. Genetic diagnoses which are not commonly associated with PIDs and not included in the International Union of Immunological Societies classification were present in 7/36 (19%): Trisomy 22, Arboleda-Tham syndrome, 2p16.3 deletion syndrome, supernumerary ring chromosome 20 syndrome, Myhre syndrome, Noonan syndrome, and trichothiodystrophy/Cockayne syndrome complex. Recurrent and/or severe infections were the most common clinical features (n = 33, 92%). Approximately half had combined immunodeficiency or antibody deficiency. The most common extra-immunological manifestations include dysmorphism (72%), disorders of nervous (78%), musculoskeletal (69%), haematology/lymphatic (58%), and gastrointestinal, hepatic/pancreatic (58%) systems.
CONCLUSIONS
Patients with sPIDs often have multiorgan involvement and some are non-immunologically mediated. There should be a low threshold to clinically assess and investigate for disorders of immunity in any patients with syndromic features especially when they present with recurrent/severe/opportunistic infections, features of immune dysregulation, autoinflammation or lymphoproliferation.
PubMed: 37568366
DOI: 10.3390/jcm12154964 -
Mechanisms of Ageing and Development 2008Nucleotide excision repair (NER) is a multi-step DNA repair mechanism that removes helix-distorting modified nucleotides from the genome. NER is divided into two... (Review)
Review
Nucleotide excision repair (NER) is a multi-step DNA repair mechanism that removes helix-distorting modified nucleotides from the genome. NER is divided into two subpathways depending on the location of DNA damage in the genome and how it is first detected. Global genome NER identifies and repairs DNA lesions throughout the genome. This subpathway of NER primarily protects against the accumulation of mutations in the genome. Transcription-coupled (TC)-NER rapidly repairs lesions in the transcribed strand of DNA that block transcription by RNA polymerase II. TC-NER prevents cell death in response to stalled transcription. Defects in NER cause three distinct human diseases: xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Each of these syndromes is characterized by premature onset of pathologies that overlap with those associated with old age in humans. This reveals the contribution of DNA damage to multiple age-related diseases. Tissues affected include the skin, eye, bone marrow, nervous system and endocrine axis. This review emphasizes accelerated aging associated with xeroderma pigmentosum and discusses the cause of these pathologies, either mutation accumulation or cell death as a consequence of failure to repair DNA damage.
Topics: Aging; Animals; Cockayne Syndrome; DNA Repair; Endocrine System; Eye Diseases; Hematopoiesis; Humans; Mice; Neoplasms; Nervous System Diseases; Skin Diseases; Trichothiodystrophy Syndromes; Xeroderma Pigmentosum
PubMed: 18538374
DOI: 10.1016/j.mad.2008.04.010 -
The Journal of Investigative Dermatology Nov 1994Xeroderma pigmentosum, Cockayne syndrome, the xeroderma pigmentosum-Cockayne syndrome complex, and trichothiodystrophy cells have defects in DNA repair and are... (Review)
Review
Xeroderma pigmentosum, Cockayne syndrome, the xeroderma pigmentosum-Cockayne syndrome complex, and trichothiodystrophy cells have defects in DNA repair and are associated with clinical and cellular hypersensitivity to ultraviolet radiation (UV). Familial dysplastic nevus syndrome cells have UV hypermutability. Although xeroderma pigmentosum and dysplastic nevus syndrome have markedly increased cancer risk. Cockayne syndrome and trichothiodystrophy do not. At the molecular level, these disorders are associated with several different genetic defects as evidenced by the existence of multiple overlapping complementation groups. Recent progress has been made in identifying the chromosomal location and cloning the defective genes in these disorders. Using plasmid shuttle vectors we have shown abnormal repair and mutagenesis of DNA damaged by 254-nm (UVC) or 295-nm (UVB) radiation or the chemical carcinogen aflatoxin in cells from patients with xeroderma pigmentosum. Although xeroderma pigmentosum cells are defective in repair of all photoproducts, Cockayne syndrome cells appear to be defective in repair of cyclobutane dimers and have normal repair of nondimer photoproducts. DNS cells have post UV plasmid hypermutability. These diseases may serve as models for examining molecular mechanisms of carcinogenesis in humans.
Topics: Cockayne Syndrome; DNA Repair; Dysplastic Nevus Syndrome; Genetic Linkage; Hair; Humans; Neoplasms; Xeroderma Pigmentosum
PubMed: 7963692
DOI: 10.1111/1523-1747.ep12399329 -
Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy: do the genes explain the diseases?Trends in Genetics : TIG May 1996Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three distinct human syndromes associated with sensitivity to ultraviolet radiation. We review... (Review)
Review
Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three distinct human syndromes associated with sensitivity to ultraviolet radiation. We review evidence that these syndromes overlap with each other and arise from mutations in genes involved in nucleotide-excision repair and RNA transcription. Attempts have been made to explain the syndromes in terms of defects in repair and transcription. These two biochemical pathways do not easily account for all the features of the syndromes. Therefore, we propose a third pathway, in which the syndromes are due, in part, to defects in a demethylation mechanism involving the excision of methylated cytosine. Perturbation of demethylation could affect the developmentally regulated expression of some genes.
Topics: Animals; Cockayne Syndrome; DNA Repair; Genes, Overlapping; Hair Diseases; Humans; Transcription, Genetic; Xeroderma Pigmentosum
PubMed: 8984734
DOI: 10.1016/0168-9525(96)10021-4 -
Human Molecular Genetics Mar 2023TFIIH is a complex essential for transcription of protein-coding genes by RNA polymerase II, DNA repair of UV-lesions and transcription of rRNA by RNA polymerase I....
TFIIH is a complex essential for transcription of protein-coding genes by RNA polymerase II, DNA repair of UV-lesions and transcription of rRNA by RNA polymerase I. Mutations in TFIIH cause the cancer prone DNA-repair disorder xeroderma pigmentosum (XP) and the developmental and premature aging disorders trichothiodystrophy (TTD) and Cockayne syndrome. A total of 50% of the TTD cases are caused by TFIIH mutations. Using TFIIH mutant patient cells from TTD and XP subjects we can show that the stress-sensitivity of the proteome is reduced in TTD, but not in XP. Using three different methods to investigate the accuracy of protein synthesis by the ribosome, we demonstrate that translational fidelity of the ribosomes of TTD, but not XP cells, is decreased. The process of ribosomal synthesis and maturation is affected in TTD cells and can lead to instable ribosomes. Isolated ribosomes from TTD patients show an elevated error rate when challenged with oxidized mRNA, explaining the oxidative hypersensitivity of TTD cells. Treatment of TTD cells with N-acetyl cysteine normalized the increased translational error-rate and restored translational fidelity. Here we describe a pathomechanism that might be relevant for our understanding of impaired development and aging-associated neurodegeneration.
Topics: Humans; Transcription Factor TFIIH; DNA Repair; Xeroderma Pigmentosum; Mutation; Trichothiodystrophy Syndromes; Ribosomes
PubMed: 36308430
DOI: 10.1093/hmg/ddac268 -
The Journal of Investigative Dermatology Oct 2009Despite their rarity, diseases of premature aging, or "progeroid" syndromes, have provided important insights into basic mechanisms that may underlie cancer and normal... (Review)
Review
Despite their rarity, diseases of premature aging, or "progeroid" syndromes, have provided important insights into basic mechanisms that may underlie cancer and normal aging. In this review, we highlight these recent developments in Hutchinson-Gilford progeria syndrome (HGPS), Werner syndrome, Bloom syndrome, Cockayne syndrome, trichothiodystrophy, ataxia-telangiectasia, Rothmund-Thomson syndrome, and xeroderma pigmentosum. Though they are caused by different mutations in various genes and often result in quite disparate phenotypes, deciphering the molecular bases of these conditions has served to highlight their underlying basic similarities. Studies of progeroid syndromes, particularly HGPS, the most dramatic form of premature aging, have contributed to our knowledge of fundamental processes of importance to skin biology, including DNA transcription, replication, and repair, genome instability, cellular senescence, and stem-cell differentiation.
Topics: Aging, Premature; Cellular Senescence; DNA Damage; Genomic Instability; Humans; Mutation; Progeria; Skin Neoplasms; Syndrome
PubMed: 19387478
DOI: 10.1038/jid.2009.103