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. We found that the XPC protein leads to selective repair of UV-induced cyclobutane pyrimidine dimers in DNA. 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 XP-G DNA repair defect leading to loss of the XPG gene. A patient with mild XP symptoms had a partially functional mutation in the XPG gene. An unusual XP-C patient had neurological abnormalities and a metabolic defect (hypoglycinemia) associated with a splice mutation. We found a common polymorphism in an intron in of the XPC gene in normal donors. 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.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC004517-26
Application #
6761422
Study Section
(BRL)
Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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
Kraemer, Kenneth H; Sander, Miriam; Bohr, Vilhelm A (2007) New areas of focus at workshop on human diseases involving DNA repair deficiency and premature aging. Mech Ageing Dev 128:229-35
Kraemer, K H; Patronas, N J; Schiffmann, R et al. (2007) Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience 145:1388-96
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
Khan, Sikandar G; Oh, Kyu-Seon; Shahlavi, Tala et al. (2006) Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients. Carcinogenesis 27:84-94
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
Liang, Christine; Morris, Andrea; Schlucker, Sebastian et al. (2006) Structural and molecular hair abnormalities in trichothiodystrophy. J Invest Dermatol 126:2210-6
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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