Reduced DNA repair in cultured melanocytes and nevus cells from a patient with xeroderma pigmentosum

Kraemer, K. H.

doi:10.1001/archderm.125.2.263

Cited by 7 publications

(4 citation statements)

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“…UVC doses of 3-12 J per m 2 (Kraemer et al, 1989), and was also quantitated by labeling wells with [ 3 H]hypoxanthine (0.5 µCi per ml, 9.1 Ci per mmol) for 2-4 h and extracting incorporated acid-insoluble radioactivity (Cleaver and Thomas, 1988). The number of repair sites per 10 7 Daltons generated intracellularly during 4 h after 13 J per m 2 was determined by blocking sites with inhibitors, followed by size determination in alkaline sucrose gradients (Cleaver, 1981).…”

Section: Methodsmentioning

confidence: 99%

Xeroderma Pigmentosum Group C Splice Mutation Associated with Autism and Hypoglycinemia11An abstract of this manuscript was presented at the annual meeting of the Society for Investigative Dermatology in Washington, DC

Khan

Levy

Legerski

et al. 1998

Journal of Investigative Dermatology

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A 4 y old boy of Korean ancestry had xeroderma pigmentosum (XP) with sun sensitivity, multiple cutaneous neoplasms, and inability to speak. Neurologic examination revealed hyperactivity and autistic features without typical XP neurologic abnormalities. Cultured skin fibroblasts (XP22BE) showed decreased post-UV survival, reduced post-UV plasmid host cell reactivation and defective DNA repair (16% of normal unscheduled DNA synthesis in intact cells and undetectable excision repair in a cell free extract). In vitro and in vivo complementation assigned XP22BE to XP group C (XPC) and a markedly reduced level of XPC mRNA was found. Two XPC cDNA bands were identified. One band had a deletion of 161 bases comprising the entire exon 9, which resulted in premature termination of the mutant XPC mRNA. The larger band also had the same deletion of exon 9 but, in addition, had an insertion of 155 bases in its place (exon 9a), resulting in an in-frame XPC mRNA. Genomic DNA analysis revealed a T-->G mutation at the splice donor site of XPC exon 9, which markedly reduced its information content. The 155 base pair XPC exon 9a insertion was located in intron 9 and was flanked by strong splice donor and acceptor sequences. Analysis of the patient's blood showed persistently low levels of glycine (68 microM; NL, 125-318 microM). Normal glycine levels were maintained with oral glycine supplements and his hyperactivity diminished. These data provide evidence of an association of an XPC splice site mutation with autistic neurologic features and hypoglycinemia.

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Section: Methodsmentioning

confidence: 99%

Xeroderma Pigmentosum Group C Splice Mutation Associated with Autism and Hypoglycinemia11An abstract of this manuscript was presented at the annual meeting of the Society for Investigative Dermatology in Washington, DC

Khan

Levy

Legerski

et al. 1998

Journal of Investigative Dermatology

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“…Sunlight, or solar radiation, is an important etiologic factor, with epidemiologic studies indicating that severe childhood sunburns contribute the greatest risk (Gilchrest et al, 1999). There is also genetic susceptibility to melanoma as demonstrated by several familial cancer syndromes, xeroderma pigmentosum (Kraemer et al, 1989), familial atypical mole and malignant melanoma syndrome (Gibbs et al, 2002), retinoblastoma (Fletcher et al, 2004), and Li-Fraumeni syndrome (Cohen et al, 2005). Melanomagenesis is associated with defects in nucleotide excision repair of solar radiation-induced DNA damage, as in xeroderma pigmentosum, and cell cycle checkpoints that arrest growth after DNA damage and oncogene activation, as in familial atypical mole and malignant melanoma syndrome, retinoblastoma, and Li-Fraumeni syndrome.…”

Section: Introductionmentioning

confidence: 99%

Defective Cell Cycle Checkpoint Functions in Melanoma Are Associated with Altered Patterns of Gene Expression

Kaufmann

Nevis

et al. 2008

Journal of Investigative Dermatology

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Defects in DNA damage responses may underlie genetic instability and malignant progression in melanoma. Cultures of normal human melanocytes (NHMs) and melanoma lines were analyzed to determine whether global patterns of gene expression could predict the efficacy of DNA damage cell cycle checkpoints that arrest growth and suppress genetic instability. NHMs displayed effective G1 and G2 checkpoint responses to ionizing radiation-induced DNA damage. A majority of melanoma cell lines (11/16) displayed significant quantitative defects in one or both checkpoints. Melanomas with B-RAF mutations as a class displayed a significant defect in DNA damage G2 checkpoint function. In contrast the epithelial-like subtype of melanomas with wild-type N-RAS and B-RAF alleles displayed an effective G2 checkpoint but a significant defect in G1 checkpoint function. RNA expression profiling revealed that melanoma lines with defects in the DNA damage G1 checkpoint displayed reduced expression of p53 transcriptional targets, such as CDKN1A and DDB2, and enhanced expression of proliferation-associated genes, such as CDC7 and GEMININ. A Bayesian analysis tool was more accurate than significance analysis of microarrays for predicting checkpoint function using a leave-one-out method. The results suggest that defects in DNA damage checkpoints may be recognized in melanomas through analysis of gene expression.

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“…Xeroderma pigmentosum patients have a high risk of melanoma. 38 Nevi related to melanoma risknumbers of nevi influenced by sun, nevi appear in sunexposed areas. [39][40][41] Red-haired phenotype associated with pheomelanin.…”

Section: Geneticsmentioning

confidence: 99%

“…Patients with the genetic disorder xeroderma pigmentosum (XP), who have an inability to repair UV-induced thymidine dimer deoxyribonucleic acid (DNA) damage, have a 1,000-fold greater risk of melanoma than their healthy cohorts. 38 Numerous studies have linked the number of nevi, whether benign or atypical, to melanoma incidence, and this appears to be a familial trait. 39 Nevi tend to appear in sunexposed areas of children and adolescents.…”

Section: Sunscreensmentioning

confidence: 99%

Role of Sun Exposure in Melanoma

2006

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Reduced DNA repair in cultured melanocytes and nevus cells from a patient with xeroderma pigmentosum

Cited by 7 publications

References 0 publications

Xeroderma Pigmentosum Group C Splice Mutation Associated with Autism and Hypoglycinemia11An abstract of this manuscript was presented at the annual meeting of the Society for Investigative Dermatology in Washington, DC

Xeroderma Pigmentosum Group C Splice Mutation Associated with Autism and Hypoglycinemia11An abstract of this manuscript was presented at the annual meeting of the Society for Investigative Dermatology in Washington, DC

Defective Cell Cycle Checkpoint Functions in Melanoma Are Associated with Altered Patterns of Gene Expression

Role of Sun Exposure in Melanoma

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