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DNA Repair Dec 2023The heterodecameric transcription factor IIH (TFIIH) functions in multiple cellular processes, foremost in nucleotide excision repair (NER) and transcription initiation... (Review)
Review
The heterodecameric transcription factor IIH (TFIIH) functions in multiple cellular processes, foremost in nucleotide excision repair (NER) and transcription initiation by RNA polymerase II. TFIIH is essential for life and hereditary mutations in TFIIH cause the devastating human syndromes xeroderma pigmentosum, Cockayne syndrome or trichothiodystrophy, or combinations of these. In NER, TFIIH binds to DNA after DNA damage is detected and, using its translocase and helicase subunits XPB and XPD, opens up the DNA and checks for the presence of DNA damage. This central activity leads to dual incision and removal of the DNA strand containing the damage, after which the resulting DNA gap is restored. In this review, we discuss new structural and mechanistic insights into the central function of TFIIH in NER. Moreover, we provide an elaborate overview of all currently known patients and diseases associated with inherited TFIIH mutations and describe how our understanding of TFIIH function in NER and transcription can explain the different disease features caused by TFIIH deficiency.
Topics: Humans; Transcription Factor TFIIH; Xeroderma Pigmentosum Group D Protein; DNA Repair; Xeroderma Pigmentosum; DNA
PubMed: 37977600
DOI: 10.1016/j.dnarep.2023.103568 -
EMBO Molecular Medicine Nov 2023The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation,...
The brittle hair syndrome Trichothiodystrophy (TTD) is characterized by variable clinical features, including photosensitivity, ichthyosis, growth retardation, microcephaly, intellectual disability, hypogonadism, and anaemia. TTD-associated mutations typically cause unstable mutant proteins involved in various steps of gene expression, severely reducing steady-state mutant protein levels. However, to date, no such link to instability of gene-expression factors for TTD-associated mutations in MPLKIP/TTDN1 has been established. Here, we present seven additional TTD individuals with MPLKIP mutations from five consanguineous families, with a newly identified MPLKIP variant in one family. By mass spectrometry-based interaction proteomics, we demonstrate that MPLKIP interacts with core splicing factors and the lariat debranching protein DBR1. MPLKIP-deficient primary fibroblasts have reduced steady-state DBR1 protein levels. Using Human Skin Equivalents (HSEs), we observed impaired keratinocyte differentiation associated with compromised splicing and eventually, an imbalanced proteome affecting skin development and, interestingly, also the immune system. Our data show that MPLKIP, through its DBR1 stabilizing role, is implicated in mRNA splicing, which is of particular importance in highly differentiated tissue.
Topics: Humans; Adaptor Proteins, Signal Transducing; Consanguinity; Mutation; Phenotype; RNA Splicing; Trichothiodystrophy Syndromes
PubMed: 37800682
DOI: 10.15252/emmm.202317973 -
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 -
Environmental and Molecular Mutagenesis Apr 2024DNA damage occurs throughout life from a variety of sources, and it is imperative to repair damage in a timely manner to maintain genome stability. Thus, DNA repair... (Review)
Review
DNA damage occurs throughout life from a variety of sources, and it is imperative to repair damage in a timely manner to maintain genome stability. Thus, DNA repair mechanisms are a fundamental part of life. Nucleotide excision repair (NER) plays an important role in the removal of bulky DNA adducts, such as cyclobutane pyrimidine dimers from ultraviolet light or DNA crosslinking damage from platinum-based chemotherapeutics, such as cisplatin. A main component for the NER pathway is transcription factor IIH (TFIIH), a multifunctional, 10-subunit protein complex with crucial roles in both transcription and NER. In transcription, TFIIH is a component of the pre-initiation complex and is important for promoter opening and the phosphorylation of RNA Polymerase II (RNA Pol II). During repair, TFIIH is important for DNA unwinding, recruitment of downstream repair factors, and verification of the bulky lesion. Several different disease states can arise from mutations within subunits of the TFIIH complex. Most strikingly are xeroderma pigmentosum (XP), XP combined with Cockayne syndrome (CS), and trichothiodystrophy (TTD). Here, we summarize the recruitment and functions of TFIIH in the two NER subpathways, global genomic (GG-NER) and transcription-coupled NER (TC-NER). We will also discuss how TFIIH's roles in the two subpathways lead to different genetic disorders.
Topics: Humans; DNA; DNA Damage; DNA Repair; Excision Repair; Transcription Factor TFIIH; Transcription, Genetic; Xeroderma Pigmentosum
PubMed: 37545038
DOI: 10.1002/em.22568 -
Cells Jul 2023Mutations in a broad variety of genes can provoke the severe childhood disorder trichothiodystrophy (TTD) that is classified as a DNA repair disease or a transcription...
Mutations in a broad variety of genes can provoke the severe childhood disorder trichothiodystrophy (TTD) that is classified as a DNA repair disease or a transcription syndrome of RNA polymerase II. In an attempt to identify the common underlying pathomechanism of TTD we performed a knockout/knockdown of the two unrelated TTD factors TTDN1 and RNF113A and investigated the consequences on ribosomal biogenesis and performance. Interestingly, interference with these TTD factors created a nearly uniform impact on RNA polymerase I transcription with downregulation of UBF, disturbed rRNA processing and reduction of the backbone of the small ribosomal subunit rRNA 18S. This was accompanied by a reduced quality of decoding in protein translation and the accumulation of misfolded and carbonylated proteins, indicating a loss of protein homeostasis (proteostasis). As the loss of proteostasis by the ribosome has been identified in the other forms of TTD, here we postulate that ribosomal dysfunction is a common underlying pathomechanism of TTD.
Topics: Humans; Child; Trichothiodystrophy Syndromes; Ribosomes; Mutation; RNA Polymerase I; Proteins; DNA-Binding Proteins
PubMed: 37508541
DOI: 10.3390/cells12141877 -
IScience Apr 2023DNA damage has long been advocated as a molecular driver of aging. DNA damage occurs in a stochastic manner, and is therefore more likely to accumulate in longer genes....
DNA damage has long been advocated as a molecular driver of aging. DNA damage occurs in a stochastic manner, and is therefore more likely to accumulate in longer genes. The length-dependent accumulation of transcription-blocking damage, unlike that of somatic mutations, should be reflected in gene expression datasets of aging. We analyzed gene expression as a function of gene length in several single-cell RNA sequencing datasets of mouse and human aging. We found a pervasive age-associated length-dependent underexpression of genes across species, tissues, and cell types. Furthermore, we observed length-dependent underexpression associated with UV-radiation and smoke exposure, and in progeroid diseases, Cockayne syndrome, and trichothiodystrophy. Finally, we studied published gene sets showing global age-related changes. Genes underexpressed with aging were significantly longer than overexpressed genes. These data highlight a previously undetected hallmark of aging and show that accumulation of genotoxicity in long genes could lead to reduced RNA polymerase II processivity.
PubMed: 37013186
DOI: 10.1016/j.isci.2023.106368 -
Central-European Journal of Immunology 2022Recurrent infections are important problems in syndromic patients. This study aimed to evaluate immunological abnormalities in patients who presented with recurrent...
INTRODUCTION
Recurrent infections are important problems in syndromic patients. This study aimed to evaluate immunological abnormalities in patients who presented with recurrent infections and were diagnosed with rare syndromes.
MATERIAL AND METHODS
This retrospective analysis included 14 patients with complaints of recurrent infections, all of whom were diagnosed with a rare syndrome.
RESULTS
The study group consisted of patients with Aicardi syndrome, Brugada syndrome, Phelan- McDermid syndrome, trichothiodystrophy, LEOPARD syndrome, Prader-Willi syndrome, Seckel syndrome, trisomy 18 (Edwards' syndrome), Wiedemann-Steiner syndrome, West syndrome, Williams syndrome, 47,XYY syndrome, 16p13 deletion syndrome, and 13q1.3 deletion syndrome. Seven patients (50%) were girls and seven (50%) were boys (mean age, 56.7 ±32.9 months; median [range] age: 45.5 [27-153] months). There were high rates of consanguinity (50%), cesarean section delivery (71%), and hospitalization in the intensive care unit (78.5%). No patients had a family history of immunodeficiency. On admission, all patients exhibited humoral and/or cellular immune system abnormalities. During the follow-up period, all T-cell abnormalities were improved after immunoglobulin replacement therapy (IGRT), while B-cell abnormalities persisted. These findings suggested that the patients predominantly had antibody deficiencies associated with mild T-cell abnormalities because of recurrent infections. The rates of infections and hospitalizations were significantly reduced after IGRT (p < 0.001); the rate of intensive care unit admission also significantly decreased (from 78.5% to 21.4%). Two of the three oxygen-dependent patients exhibited improvement therein. IGRT was discontinued in two patients with significant clinical improvement during follow-up.
CONCLUSIONS
An immunological evaluation should be considered in pediatric patients with rare syndromes and recurrent infections. IGRT may help to improve the prognoses of these patients.
PubMed: 36817395
DOI: 10.5114/ceji.2022.124080 -
Pediatric Neurology Apr 2023Cockayne syndrome (CS) is a DNA repair disorder primarily associated with pathogenic variants in ERCC6 and ERCC8. As in other Mendelian disorders, there are a number of...
BACKGROUND
Cockayne syndrome (CS) is a DNA repair disorder primarily associated with pathogenic variants in ERCC6 and ERCC8. As in other Mendelian disorders, there are a number of genetically unsolved CS cases.
METHODS
We ascertained five individuals with monoallelic pathogenic variants in MORC2, previously associated with three dominantly inherited phenotypes: an axonal form of Charcot-Marie-Tooth disease type 2Z; a syndrome of developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy; and a rare form of spinal muscular atrophy.
RESULTS
One of these individuals bore a strong phenotypic resemblance to CS. We then identified monoallelic pathogenic MORC2 variants in three of five genetically unsolved individuals with a clinical diagnosis of CS. In total, we identified eight individuals with MORC2-related disorder, four of whom had clinical features strongly suggestive of CS.
CONCLUSIONS
Our findings indicate that some forms of MORC2-related disorder have phenotypic similarities to CS, including features of accelerated aging. Unlike classic DNA repair disorders, MORC2-related disorder does not appear to be associated with a defect in transcription-coupled nucleotide excision repair and follows a dominant pattern of inheritance with variants typically arising de novo. Such de novo pathogenic variants present particular challenges with regard to both initial gene discovery and diagnostic evaluations. MORC2 should be included in diagnostic genetic test panels targeting the evaluation of microcephaly and/or suspected DNA repair disorders. Future studies of MORC2 and its protein product, coupled with further phenotypic characterization, will help to optimize the diagnosis, understanding, and therapy of the associated disorders.
Topics: Humans; Cockayne Syndrome; DNA Repair Enzymes; Phenotype; Microcephaly; Mutation; Transcription Factors
PubMed: 36791574
DOI: 10.1016/j.pediatrneurol.2023.01.011 -
Antibiotics (Basel, Switzerland) Dec 2022An 8-year-old girl diagnosed with cardiofaciocutaneous syndrome presented to our department with gingival pain, inflammation, and bleeding. Her medical history included...
An 8-year-old girl diagnosed with cardiofaciocutaneous syndrome presented to our department with gingival pain, inflammation, and bleeding. Her medical history included hypoplasia of the corpus callosum, intellectual disability, trichothiodystrophy, global developmental delay, myopia, laryngomalacia, hypothyroidism, and osteoporosis. A diagnosis was reached of "periodontitis as a direct manifestation of systemic diseases". During 9 years of follow-up, there were exacerbation episodes with spontaneous gum bleeding, ulcers in the interdental papilla, tooth mobility, and progressive tooth loss. Some of these exacerbation episodes resolved clinically with the administration of amoxicillin and metronidazole. We therefore proposed an oral microbiome study (subgingival and saliva samples) before and after antibiotic therapy. The most abundant genera at the subgingival level before administering antibiotics were , , , and . Of the 94 genera sequenced, 57 were less abundant in the post-treatment state than at baseline, particularly certain Gram-negative periodontal pathogens such as and . In contrast, other genera related to oral health, such as and , showed an increase after administering the antibiotic. In conclusion, periodontitis exacerbations as a direct manifestation of systemic disease can occasionally be controlled exclusively with systemic antibiotics, without the need for performing mechanical periodontal therapy. This clinical recovery is correlated to substantial changes in the oral microbiome, which lead to the recovery of eubiosis of the microbiota.
PubMed: 36551411
DOI: 10.3390/antibiotics11121754