A summary of mutations in the UV-sensitive disorders: Xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy

Cleaver, James E.; Thompson, Larry H.; Richardson, Audrey S.; States, J. Christopher

doi:10.1002/(sici)1098-1004(1999)14:1<9::aid-humu2>3.0.co;2-6

Cited by 205 publications

(102 citation statements)

References 100 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The disease begins in early life with the first exposure to sunlight, the median age of onset being 1-2 years of age, with skin rapidly exhibiting the signs associated with years of sun exposure. 1,3,4 The disorder is due to inactivation of the XPC protein, an important DNA damage recognition protein involved in NER, a highly versatile system capable of removing a wide variety of helix-distorting lesions from genomic DNA. 5 This system includes two distinct subpathways: global genome repair (GGR), which repairs DNA damage throughout the genome; and transcription-coupled repair (TCR), which repairs DNA lesions in the transcribed strand of active genes.…”

Section: Introductionsupporting

confidence: 92%

“…As a consequence, XPC inactivation results in sun sensitivity and increased risk of skin cancer (2000-fold increased incidence). [3][4][5] In agreement with previous findings, [32][33][34] the patients in this study had no detectable XPC protein in keratinocytes obtained from skin biopsies, and two functional mutants (c1639delTG and pR220X) of the XPC gene were identified. Recent unpublished data from our laboratory have shown that the (c1639delTG) mutant is highly prevalent in XP patients from North Africa, and is associated with a high level of consanguinity.…”

Section: Xpc Gene Defectmentioning

confidence: 99%

See 1 more Smart Citation

Catalase overexpression reduces UVB-induced apoptosis in a human xeroderma pigmentosum reconstructed epidermis

et al. 2008

View full text Add to dashboard Cite

Xeroderma pigmentosum type C (XPC) is a rare autosomal recessive disorder that occurs due to inactivation of the XPC protein, an important DNA damage recognition protein involved in DNA nucleotide excision repair (NER). This defect, which prevents removal of a wide array of direct and indirect DNA lesions, is associated with a decrease in catalase activity. To test the hypothesis of a novel photoprotective approach, we irradiated epidermis reconstructed with XPC human keratinocytes sustainably overexpressing lentivirus-mediated catalase enzyme. Following UVB irradiation, there was a marked decrease in sunburn cell formation, caspase-3 activation and p53 accumulation in human XPC-reconstructed epidermis overexpressing catalase. Moreover, XPC-reconstructed epidermis was more resistant to UVB-induced apoptosis than normal reconstructed epidermis. While not correcting the gene defect, indirect gene therapy using antioxidant enzymes may be of help in limiting photosensitivity in XPC and probably in other monogenic/polygenic photosensitive disorders characterized by ROS accumulation.

show abstract

Section: Introductionsupporting

confidence: 92%

Section: Xpc Gene Defectmentioning

confidence: 99%

Catalase overexpression reduces UVB-induced apoptosis in a human xeroderma pigmentosum reconstructed epidermis

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Defects in these repair mechanisms can lead to severe disorders such as xeroderma pigmentosum, ataxia telangiectasia, Fanconi anemia, and Bloom syndrome (reviewed in refs. [1][2][3][4][5]. One of the major consequences of these defects is an enhanced predisposition to cancer.…”

supporting

confidence: 93%

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

Vásquez

Christensen

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

111

128

View full text Add to dashboard Cite

Nucleotide excision repair (NER) plays a central role in maintaining genomic integrity by detecting and repairing a wide variety of DNA lesions. Xeroderma pigmentosum complementation group A protein (XPA) is an essential component of the repair machinery, and it is thought to be involved in the initial step as a DNA damage recognition and͞or confirmation factor. Human replication protein A (RPA) and XPA have been reported to interact to form a DNA damage recognition complex with greater specificity for damaged DNA than XPA alone. The mechanism by which these two proteins recognize such a wide array of structures resulting from different types of DNA damage is not known. One possibility is that they recognize a common feature of the lesions, such as distortions of the helical backbone. We have tested this idea by determining whether human XPA and RPA proteins can recognize the helical distortions induced by a DNA triple helix, a noncanonical DNA structure that has been shown to induce DNA repair, mutagenesis, and recombination. We measured binding of XPA and RPA, together or separately, to substrates containing triplexes with three, two, or no strands covalently linked by psoralen conjugation and photoaddition. We found that RPA alone recognizes all covalent triplex structures, but also forms multivalent nonspecific DNA aggregates at higher concentrations. XPA by itself does not recognize the substrates, but it binds them in the presence of RPA. Addition of XPA decreases the nonspecific DNA aggregate formation. These results support the hypothesis that the NER machinery is targeted to helical distortions and demonstrate that RPA can recognize damaged DNA even without XPA.triple helix ͉ nucleotide excision repair B ecause genome stability is critical for cell survival, extremely sensitive DNA repair mechanisms have evolved to protect the genome from both internal and external assaults. Defects in these repair mechanisms can lead to severe disorders such as xeroderma pigmentosum, ataxia telangiectasia, Fanconi anemia, and Bloom syndrome (reviewed in refs. 1-5). One of the major consequences of these defects is an enhanced predisposition to cancer. It has been reported that 80-90% of human cancers are the result of DNA damage (6).Many types of DNA damage, spontaneous and induced, develop from both endogenous and exogenous sources. Exogenous damages, both chemical and physical, arise from exposure to UV and ionizing radiation and from natural and synthetic chemicals. Cellular metabolic processes lead to internal sources of DNA damage; for example, it is estimated that loss of a purine base (depurination) occurs at a rate of nearly 20,000 events per cell per day (7).In humans, different types of DNA damage are thought to be repaired by one of several mechanisms, including nucleotide excision repair (NER; reviewed in refs. 8 and 9). NER removes covalent DNA lesions and is the only known mechanism for removing bulky DNA adducts in humans. The damaged base is removed by endonucleolytic cleavage of the phosphodiester bond...

show abstract

“…Moreover, DDB2 has been shown to participate in global nucleotide excision repair (NER) (Hwang et al, 1998a;Tang et al, 2000;Wakasugi et al, 2002). The proteins involved in the NER pathway are mutated in the eight different complementation groups of the repair-deficiency disease xeroderma pigmentosum (XP: A-G and V) (Friedberg et al, 1995;Sancar, 1996;Cleaver et al, 1999). XP is a rare autosomal recessive disease characterized by sun-sensitivity and a high incidence of skin malignancies, and these phenotypes are believed to arise from a deficiency in the NER pathway of DNA repair.…”

Section: Introductionmentioning

confidence: 99%

Tumor-prone phenotype of the DDB2-deficient mice

et al. 2004

View full text Add to dashboard Cite

DDB2 is an essential subunit of the damaged-DNA recognition factor DDB, which is involved in global genomic repair in human cells. Moreover, DDB2 is mutated in the repair-deficiency disease xeroderma pigmentosum (Group E). Expression of DDB2 in human cells is induced by P53, BRCA1 and by ionizing radiation. The DDB2 protein associates with transcriptional activator and coactivator proteins. In addition, DDB2 in conjunction with DDB1 associates with cullin 4A and the Cop9/signalosome. We generated a mouse strain deficient for DDB2 (DDB2À/À). Consistent with the human disease (XP-E), the DDB2À/À mice were susceptible to UV-induced skin carcinogenesis. We observed a significant difference in the initial rate of cyclobutane pyrimidine dimer (CPD)-removal from the skin following UV irradiation. Also, the DDB2-deficient mice exhibited a significantly reduced life span compared to their wild-type littermates. Moreover, unlike other XP-deficient mice, the DDB2-deficient mice developed spontaneous malignant tumors at a high rate between the ages of 20 and 25 months. The observations suggest that, in addition to DNA repair, the other interactions of DDB2 are significant in its tumor suppression function.

show abstract

A summary of mutations in the UV-sensitive disorders: Xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy

Cited by 205 publications

References 100 publications

Catalase overexpression reduces UVB-induced apoptosis in a human xeroderma pigmentosum reconstructed epidermis

Catalase overexpression reduces UVB-induced apoptosis in a human xeroderma pigmentosum reconstructed epidermis

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

Tumor-prone phenotype of the DDB2-deficient mice

Contact Info

Product

Resources

About