Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 15, Pages 6209-6214Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0902113106
Keywords
Cockayne syndrome; DNA repair; transcription-coupled repair; ultraviolet radiation
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Funding
- European Community [LSHM-CT-2005-512117]
- Associazione Italiana per la Ricerca sul Cancro
- Fondazione Cariplo
- Istituto Superiore Sanita` - Programma Malattie Rare
- National Cancer Institute [CA91456]
- Agence Nationale de la Recherche and Ligue Contre le Cancer ( Paris)
- Association de Recherche sur le Cancer
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UV-sensitive syndrome ((UVS)-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. UVSS 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 UVSS 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 UVSS1VI 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 (UVS)-S-s patients that are limited to skin photosensitivity without precocious aging or neurodegeneration.
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