Nardo T, Oneda R, Spivak G et al.A UV-sensitive syndrome patient with a specific CSA mutation reveals separable roles for CSA in response to UV and oxidative DNA damage. Proc Natl Acad Sci USA 106:6209-6214

Istituto di Genetica Molecolare, Consiglio Nazionale delle Ricerche, via Abbiategrasso 207, 27100 Pavia, Italy.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2009; 106(15):6209-14. DOI: 10.1073/pnas.0902113106
Source: PubMed


UV-sensitive syndrome (UV(S)S) is a recently-identified autosomal recessive disorder characterized by mild cutaneous symptoms and defective transcription-coupled repair (TC-NER), the subpathway of nucleotide excision repair (NER) that rapidly removes damage that can block progression of the transcription machinery in actively-transcribed regions of DNA. Cockayne syndrome (CS) is another genetic disorder with sun sensitivity and defective TC-NER, caused by mutations in the CSA or CSB genes. The clinical hallmarks of CS include neurological/developmental abnormalities and premature aging. UV(S)S is genetically heterogeneous, in that it appears in individuals with mutations in CSB or in a still-unidentified gene. We report the identification of a UV(S)S patient (UV(S)S1VI) with a novel mutation in the CSA gene (p.trp361cys) that confers hypersensitivity to UV light, but not to inducers of oxidative damage that are notably cytotoxic in cells from CS patients. The defect in UV(S)S1VI cells is corrected by expression of the WT CSA gene. Expression of the p.trp361cys-mutated CSA cDNA increases the resistance of cells from a CS-A patient to oxidative stress, but does not correct their UV hypersensitivity. These findings imply that some mutations in the CSA gene may interfere with the TC-NER-dependent removal of UV-induced damage without affecting its role in the oxidative stress response. The differential sensitivity toward oxidative stress might explain the difference between the range and severity of symptoms in CS and the mild manifestations in UV(s)S patients that are limited to skin photosensitivity without precocious aging or neurodegeneration.

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Available from: Donata Orioli, Mar 28, 2014
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    • "Adducts with similar structural and thermodynamic features can be formed by active metabolites of environmental and dietary compounds (such as arylamines and heterocyclic amines), raising a possibility that manifestation of the clinical features of CS can be influenced by environmental exposures and the individual metabolic phenotype. This would explain the lack of good correlation between the patients' genotype and the severity of the disease [5], including the absence of the characteristic CS phenotype in a few described cases [30], [31]. "
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    ABSTRACT: Hereditary defects in the transcription-coupled nucleotide excision repair (TC-NER) pathway of damaged DNA cause severe neurodegenerative disease Cockayne syndrome (CS), however the origin and chemical nature of the underlying DNA damage had remained unknown. To find out, to which degree the structural properties of DNA lesions determine the extent of transcription arrest in human CS cells, we performed quantitative host cell reactivation analyses of expression vectors containing various synthetic adducts. We found that a single 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorene adduct (dG(N2)-AAF) constitutes an unsurmountable obstacle to transcription in both CS-A and CS-B cells and is removed exclusively by the CSA- and CSB-dependent pathway. In contrast, contribution of the CS proteins to the removal of two other transcription-blocking DNA lesions - N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG(C8)-AAF) and cyclobutane thymine-thymine (TT) dimer - is only minor (TT dimer) or none (dG(C8)-AAF). The unique properties of dG(N2)-AAF identify this adduct as a prototype for a new class of DNA lesions that escape the alternative global genome repair and could be critical for the CS pathogenesis.
    PLoS ONE 04/2014; 9(4):e94405. DOI:10.1371/journal.pone.0094405 · 3.23 Impact Factor
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    • "Although both CS-B and UVSS cells are defective in the recovery of UV-irradiated plasmids, only CS-B cells recover gene expression through plasmids carrying oxidized base damage (Spivak and Hanawalt, 2006). Moreover, a UVSS patient was demonstrated to have a specific mutation in the CS-A gene, and cells derived from this patient were highly sensitive to UV irradiation; however, in contrast to CS-A cells from CS patients, these UVSS cells were not sensitive to potassium bromate or other agents that generate oxidative stress (Nardo et al., 2009). Similar results were obtained in XP patients carrying missense mutations in the XPG gene. "
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    ABSTRACT: The discovery of DNA repair defects in human syndromes, initially in xeroderma pigmentosum (XP) but later in many others, led to striking observations on the association of molecular defects and patients' clinical phenotypes. For example, patients with syndromes resulting from defective nucleotide excision repair (NER) or translesion synthesis (TLS) present high levels of skin cancer in areas exposed to sunlight. However, some defects in NER also lead to more severe symptoms, such as developmental and neurological impairment and signs of premature aging. Skin cancer in XP patients is clearly associated with increased mutagenesis and genomic instability, reflecting the defective repair of DNA lesions. By analogy, more severe symptoms observed in NER-defective patients have also been associated with defective repair, likely involving cell death after transcription blockage of damaged templates. Endogenously induced DNA lesions, particularly through oxidative stress, have been identified as responsible for these severe pathologies. However, this association is not that clear and alternative explanations have been proposed. Despite high levels of exposure to intense sunlight, patients from tropical countries receive little attention or care, which likely also reflects the lack of understanding of how DNA damage causes cancer and premature aging.
    Genetics and Molecular Biology 03/2014; 37(1 Suppl):220-233. DOI:10.1590/S1415-47572014000200008 · 1.20 Impact Factor
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    • "Surprisingly , the mild clinical manifestations were associated with a cellular DNA repair defect similar to that seen in CS patients (i.e., proficient GG-NER and defective TC-NER), expressed as the inability to recover RNA synthesis (RRS) after UV and defective transcription-coupled excision repair of the major UV lesion (CPD) (Spivak et al. 2002). This difference in phenotypic expression despite a similar TC-NER defect is particularly striking because two patients carry mutations in either the CSB (Horibata et al. 2004) or CSA genes (Nardo et al. 2009). The few other patients belong to a separate complementation group designated UV S S- A, of which the implicated gene was unknown until recently. "
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    ABSTRACT: Transcriptional arrest caused by DNA damage is detrimental for cells and organisms as it impinges on gene expression and thereby on cell growth and survival. To alleviate transcriptional arrest, cells trigger a transcription-dependent genome surveillance pathway, termed transcription-coupled nucleotide excision repair (TC-NER) that ensures rapid removal of such transcription-impeding DNA lesions and prevents persistent stalling of transcription. Defective TC-NER is causatively linked to Cockayne syndrome, a rare severe genetic disorder with multisystem abnormalities that results in patients' death in early adulthood. Here we review recent data on how damage-arrested transcription is actively coupled to TC-NER in mammals and discuss new emerging models concerning the role of TC-NER-specific factors in this process.
    Cold Spring Harbor perspectives in biology 08/2013; 5(8). DOI:10.1101/cshperspect.a012625 · 8.68 Impact Factor
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