The laboratory is studying molecular, cellular and clinical abnormalities in human cancer-prone genetic diseases. Current studies are focusing on xeroderma pigmentosum (XP) a cancer-prone genetic disease with cellular hypersensitivity to environmental agents. We developed new assays using plasmids to measure DNA repair and mutagenesis at the molecular level in human cells and to assign cells to XP complementation groups. A shuttle vector plasmid replicated in a mismatch repair defective human cell line showed sequence-dependent mutations. Studies of lymphoblastoid cells from normal donors showed increased plasmid UV mutability with increasing donor age indicating that aging is associated with decreasing ability to repair DNA damage. We identified several unusual XP patients. Cells from a patient with the rare xeroderma pigmentosum/ Cockayne syndrome complex with severe clinical symptoms of Cockayne syndrome had the cellular characteristics of the XP-G DNA repair defect. An unusual XP-C patient had neurological abnormalities and a metabolic defect (hypoglycinemia) associated with a splice mutation. Chemoprevention of skin cancer in XP with oral 13-cis retinoic acid was found to be effective in preventing skin cancers but very toxic. The lowest effective dose varied in different patients. - aging, DNA repair, melanoma, Plasmids, skin cancer, UV mutagenesis, xeroderma pigmentosum, Cancer genetics, Cancer Prevention, chemoprevention, Gene Mutation, Genetic polymorphism, - Human Subjects

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Emmert, Steffen; Kraemer, Kenneth H (2013) Do not underestimate nucleotide excision repair: it predicts not only melanoma risk but also survival outcome. J Invest Dermatol 133:1713-7
Wang, Yun; Digiovanna, John J; Stern, Jere B et al. (2009) Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas. Proc Natl Acad Sci U S A 106:6279-84
Oh, Kyu-Seon; Imoto, Kyoko; Boyle, Jennifer et al. (2007) Influence of XPB helicase on recruitment and redistribution of nucleotide excision repair proteins at sites of UV-induced DNA damage. DNA Repair (Amst) 6:1359-70
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Schlucker, S; Liang, C; Strehle, K R et al. (2006) Conformational differences in protein disulfide linkages between normal hair and hair from subjects with trichothiodystrophy: a quantitative analysis by Raman microspectroscopy. Biopolymers 82:615-22
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Emmert, Steffen; Wetzig, Tino; Imoto, Kyoko et al. (2006) A novel complex insertion/deletion mutation in the XPC DNA repair gene leads to skin cancer in an Iraqi family. J Invest Dermatol 126:2542-4
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Hirai, Yuko; Kodama, Yoshiaki; Moriwaki, Shin-Ichi et al. (2006) Heterozygous individuals bearing a founder mutation in the XPA DNA repair gene comprise nearly 1% of the Japanese population. Mutat Res 601:171-8

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