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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Syndromes involving premature skin aging provide outstanding models for a better understanding of both skin senescence and of the aging process in general. Although initially merely descriptive, these rare or indeed very rare conditions have been studied in detail and their genetic and biochemical background has been elucidated. The new data are now sufficiently accurate to allow the development of a new classification based on the underlying biochemical pathomechanisms. Three main subsets can be distinguished: progeroid syndromes with direct or indirect impairment of lamin A (progeria), syndromes involving dysfunction of the excision/repair apparatus (Cockayne syndrome), and conditions involving chromosome instability, particularly in the event of helicase mutation (Werner and Rothmund-Thomson syndromes, ataxia-telangiectasia). The diagnosis is still based on clinical examination in most cases, with the dermatologist commonly playing a key role because of the frequently obvious nature of skin changes, whereas other abnormalities may be less clear-cut or initially absent. Specialized genetic studies to confirm phenotypic hypothesis are increasingly available thanks to the development of reference centres. Although treatment continues to be symptomatic in most cases, recent advances in basic research have raised new hopes regarding targeted therapies, notably in progeria.
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PMID:[Premature aging syndromes : From phenotype to gene]. 1859 96

The premature ageing ataxia telangiectasia (AT) and Werner syndromes (WS) are associated with accelerated cellular ageing. Young WS fibroblasts have an aged appearance and activated p38 MAP kinase, and treatment with the p38 inhibitor SB230580 extends their lifespan to within the normal range. SB203580 also extends the replicative lifespan of normal adult dermal fibroblasts, however, the effect is much reduced when compared to WS cells, suggesting that WS fibroblasts undergo a form of stress-induced premature senescence (SIPS). A small lifespan extension is seen in AT cells, which is not significant compared to normal fibroblasts, and the majority of young AT cells do not have an aged appearance and lack p38 activation, suggesting that the premature ageing does not result from SIPS. The lack of p38 activation is supported by the clinical manifestation, since AT is not associated with inflammatory disease, whereas WS individuals are predisposed to atherosclerosis, type II diabetes and osteoporosis, conditions known to be associated with p38 activation.
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PMID:Assessing the role of stress signalling via p38 MAP kinase in the premature senescence of ataxia telangiectasia and Werner syndrome fibroblasts. 1883 Jun 81

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.
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PMID:From the rarest to the most common: insights from progeroid syndromes into skin cancer and aging. 1938 78

Bloom syndrome confers strong predisposition to malignancy in multiple tissue types. The Bloom syndrome patient (BLM) protein defective in the disease biochemically functions as a Holliday junction dissolvase and human cells lacking functional BLM show 10-fold elevated rates of sister chromatid exchange. Collectively, these phenomena suggest that dysregulated mitotic recombination drives the genomic instability underpinning the development of cancer in these individuals. Here we use physical analysis of the highly repeated, highly self-similar human ribosomal RNA gene clusters as sentinel biomarkers for dysregulated homologous recombination to demonstrate that loss of BLM protein function causes a striking increase in spontaneous molecular level genomic restructuring. Analysis of single-cell derived sub-clonal populations from wild-type human cell lines shows that gene cluster architecture is ordinarily very faithfully preserved under mitosis, but is so unstable in cell lines derived from BLMs as to make gene cluster architecture in different sub-clonal populations essentially unrecognizable one from another. Human cells defective in a different RecQ helicase, the WRN protein involved in the premature aging Werner syndrome, do not exhibit the gene cluster instability (GCI) phenotype, indicating that the BLM protein specifically, rather than RecQ helicases generally, holds back this recombination-mediated genomic instability. An ataxia-telangiectasia defective cell line also shows elevated rDNA GCI, although not to the extent of BLM defective cells. Genomic restructuring mediated by dysregulated recombination between the abundant low-copy repeats in the human genome may prove to be an important additional mechanism of genomic instability driving the initiation and progression of human cancer.
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PMID:Loss of Bloom syndrome protein destabilizes human gene cluster architecture. 1954 97

Progeroid syndromes are a group of diseases characterized by signs of premature aging. These syndromes comprise diseases such as Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford syndrome, Fanconi anemia, and ataxia-telangiectasia, as well as xeroderma pigmentosum, trichothiodystrophy, and Cockayne syndrome. Clinical symptoms of premature aging are skin atrophy with loss of cutaneous elasticity, dysfunction of cutaneous appendices, degeneration of the central nervous system and an increased susceptibility for malignant tumors. Genetic defects in the repair of DNA damage can lead to progeroid syndromes, and it is becoming increasingly evident that direct DNA damage and indirect damage by highly reactive oxygen species play central roles in aging. The clinical signs of progeroid syndromes and the molecular aspects of UV (ultraviolet radiation)-induced oxidative stress in aging are discussed.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 8-14; doi:10.1038/jidsymp.2009.6.
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PMID:Progeroid syndromes and UV-induced oxidative DNA damage. 1967 46

WRN-1 is the Caenorhabditis elegans homolog of the human Werner syndrome protein, a RecQ helicase, mutations of which are associated with premature aging and increased genome instability. Relatively little is known as to how WRN-1 functions in DNA repair and DNA damage signaling. Here, we take advantage of the genetic and cytological approaches in C. elegans to dissect the epistatic relationship of WRN-1 in various DNA damage checkpoint pathways. We found that WRN-1 is required for CHK1 phosphorylation induced by DNA replication inhibition, but not by UV radiation. Furthermore, WRN-1 influences the RPA-1 focus formation, suggesting that WRN-1 functions in the same step or upstream of RPA-1 in the DNA replication checkpoint pathway. In response to ionizing radiation, RPA-1 focus formation and nuclear localization of ATM depend on WRN-1 and MRE-11. We conclude that C. elegans WRN-1 participates in the initial stages of checkpoint activation induced by DNA replication inhibition and ionizing radiation. These functions of WRN-1 in upstream DNA damage signaling are likely to be conserved, but might be cryptic in human systems due to functional redundancy.
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PMID:The Caenorhabditis elegans Werner syndrome protein functions upstream of ATR and ATM in response to DNA replication inhibition and double-strand DNA breaks. 2006 19

Rothmund-Thomson syndrome (RTS) is a genodermatosis presenting with a characteristic facial rash (poikiloderma) associated with short stature, sparse scalp hair, sparse or absent eyelashes and/or eyebrows, juvenile cataracts, skeletal abnormalities, radial ray defects, premature aging and a predisposition to cancer. The prevalence is unknown but around 300 cases have been reported in the literature so far. The diagnostic hallmark is facial erythema, which spreads to the extremities but spares the trunk, and which manifests itself within the first year and then develops into poikiloderma. Two clinical subforms of RTS have been defined: RTSI characterised by poikiloderma, ectodermal dysplasia and juvenile cataracts, and RTSII characterised by poikiloderma, congenital bone defects and an increased risk of osteosarcoma in childhood and skin cancer later in life. The skeletal abnormalities may be overt (frontal bossing, saddle nose and congenital radial ray defects), and/or subtle (visible only by radiographic analysis). Gastrointestinal, respiratory and haematological signs have been reported in a few patients. RTS is transmitted in an autosomal recessive manner and is genetically heterogeneous: RTSII is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (detected in 60-65% of RTS patients), whereas the aetiology in RTSI remains unknown. Diagnosis is based on clinical findings (primarily on the age of onset, spreading and appearance of the poikiloderma) and molecular analysis for RECQL4 mutations. Missense mutations are rare, while frameshift, nonsense mutations and splice-site mutations prevail. A fully informative test requires transcript analysis not to overlook intronic deletions causing missplicing. The diagnosis of RTS should be considered in all patients with osteosarcoma, particularly if associated with skin changes. The differential diagnosis should include other causes of childhood poikiloderma (including dyskeratosis congenita, Kindler syndrome and Poikiloderma with Neutropaenia), other rare genodermatoses with prominent telangiectasias (including Bloom syndrome, Werner syndrome and Ataxia-telangiectasia) and the allelic disorders, RAPADILINO syndrome and Baller-Gerold syndrome, which also share some clinical features. A few mutations recur in all three RECQL4 diseases. Genetic counselling should be provided for RTS patients and their families, together with a recommendation for cancer surveillance for all patients with RTSII. Patients should be managed by a multidisciplinary team and offered long term follow-up. Treatment includes the use of pulsed dye laser photocoagulation to improve the telangiectatic component of the rash, surgical removal of the cataracts and standard treatment for individuals who develop cancer. Although some clinical signs suggest precocious aging, life expectancy is not impaired in RTS patients if they do not develop cancer. Outcomes in patients with osteosarcoma are similar in RTS and non-RTS patients, with a five-year survival rate of 60-70%. The sensitivity of RTS cells to genotoxic agents exploiting cells with a known RECQL4 status is being elucidated and is aimed at optimizing the chemotherapeutic regimen for osteosarcoma.
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PMID:Rothmund-Thomson syndrome. 2011 79

Rothmund-Thomson syndrome (RTS) is an autosomal recessive hereditary disorder associated with mutation in RECQL4 gene, a member of the human RecQ helicases. The disease is characterized by genomic instability, skeletal abnormalities and predisposition to malignant tumors, especially osteosarcomas. The precise role of RECQL4 in cellular pathways is largely unknown; however, recent evidence suggests its involvement in multiple DNA metabolic pathways. This study investigates the roles of RECQL4 in DNA double-strand break (DSB) repair. The results show that RECQL4-deficient fibroblasts are moderately sensitive to gamma-irradiation and accumulate more gammaH2AX and 53BP1 foci than control fibroblasts. This is suggestive of defects in efficient repair of DSB's in the RECQL4-deficient fibroblasts. Real time imaging of live cells using laser confocal microscopy shows that RECQL4 is recruited early to laser-induced DSBs and remains for a shorter duration than WRN and BLM, indicating its distinct role in repair of DSBs. Endogenous RECQL4 also colocalizes with gammaH2AX at the site of DSBs. The RECQL4 domain responsible for its DNA damage localization has been mapped to the unique N-terminus domain between amino acids 363-492, which shares no homology to recruitment domains of WRN and BLM to the DSBs. Further, the recruitment of RECQL4 to laser-induced DNA damage is independent of functional WRN, BLM or ATM proteins. These results suggest distinct cellular dynamics for RECQL4 protein at the site of laser-induced DSB and that it might play important roles in efficient repair of DSB's.
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PMID:The involvement of human RECQL4 in DNA double-strand break repair. 2022 2

Oxidative stress is a phenotypic hallmark in several genetic disorders characterized by cancer predisposition and/or propensity to premature ageing. Here we review the published evidence for the involvement of oxidative stress in the phenotypes of Ataxia-Telangiectasia (A-T), Down Syndrome (DS), Fanconi Anaemia (FA), and Werner Syndrome (WS), from the viewpoint of mitochondrial dysfunction. Mitochondria are recognized as both the cell compartment where energetic metabolism occurs and as the first and most susceptible target of reactive oxygen species (ROS) formation. Thus, a critical evaluation of the basic mechanisms leading to an in vivo pro-oxidant state relies on elucidating the features of mitochondrial impairment in each disorder. The evidence for different mitochondrial dysfunctions reported in A-T, DS, and FA is reviewed. In the case of WS, clear-cut evidence linking human WS phenotype to mitochondrial abnormalities is lacking so far in the literature. Nevertheless, evidence relating mitochondrial dysfunctions to normal ageing suggests that WS, as a progeroid syndrome, is likely to feature mitochondrial abnormalities. Hence, ad hoc research focused on elucidating the nature of mitochondrial dysfunction in WS pathogenesis is required. Based on the recognized, or reasonably suspected, role of mitochondrial abnormalities in the pathogenesis of these disorders, studies of chemoprevention with mitochondria-targeted supplements are warranted.
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PMID:Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome. 2023 55

Werner syndrome (WS), caused by mutation of the WRN gene, is an autosomal recessive disorder associated with premature aging and predisposition to cancer. WRN belongs to the RecQ DNA helicase family, members of which play a role in maintaining genomic stability. Here, we demonstrate that WRN rapidly forms discrete nuclear foci in an NBS1-dependent manner following DNA damage. NBS1 physically interacts with WRN through its FHA domain, which interaction is important for the phosphorylation of WRN. WRN subsequently forms DNA damage-dependent foci during the S phase, but not in the G1 phase. WS cells exhibit an increase in spontaneous focus formation of poleta and Rad18, which are important for translesion synthesis (TLS). WRN also interacts with PCNA in the absence of DNA damage, but DNA damage induces the dissociation of PCNA from WRN, leading to the ubiquitination of PCNA, which is essential for TLS. This dissociation correlates with ATM/NBS1-dependent degradation of WRN. Moreover, WS cells show constitutive ubiquitination of PCNA and interaction between PCNA and Rad18 E3 ligase in the absence of DNA damage. Taken together, these results indicate that WRN participates in the TLS pathway to prevent genomic instability in an ATM/NBS1-dependent manner.
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PMID:WRN participates in translesion synthesis pathway through interaction with NBS1. 2060 Feb 38


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