Human health risks from environmental carcinogens and genotoxic agents are modified by a range of specific gene families and polymorphisms. Progress in understanding these genes has come through genetic diseases that show increased susceptibility to environmental agents, especially ultraviolet light, and in which DNA repair mechanisms play a pivotal role. Xeroderma pigmentosum and related diseases such as Cockayne syndrome and trichothiodystrophy have been extremely informative about the role of DNA damage and excision repair in carcinogenesis, and have revealed a fundamental linkage between repair and gene transcription which may explain varied clinical symptoms involving neurological and developmental disorders. Less well understood are mechanisms by which damaged DNA is faithfully replicated by several human diseases appear to represent defects in replication fidelity and cell cycle control. These diseases which show increases susceptibility to cancer and chromosomal and genetic instability include ataxia telangiectasia, Bloom syndrome, dysplastic nevus syndrome and the XP variant. The XP variant is of especial interest because the clinical symptoms of actinic carcinogenesis and occasional cases of neurological decline are indistinguishable from excision defective XP groups A through G, yet cells show normal excision reaper. The XP variant therefore represents a linkage between the processing of DNA damage and the fidelity of DNA replication and repair whereas the other XP groups represent reductions in quantitative aspects of repair. We propose a study that will lead to cloning the XP variant and related genes and understanding its biochemistry. We have already detected increased chromosome instability that is distinctive for SV40 transformed XP variants, suggesting that the XPV gene product lies on T antigen-dependent pathways. Preliminary evidence has already provided us new insights into relationship between the XPV phenotype, the biochemical pathways of methyl transfer and genetic instability; we have cloned one gene involved in expression of increased SCES in variant cells, which is homologous to a homocysteine hydrolase and is on chromosome 1 and has alterations in its 3'utr in 2 XPV cell lines, and present strategies for identifying additional genes involved in the XPV phenotype.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008061-02
Application #
2908982
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Pelroy, Richard
Project Start
1998-02-01
Project End
2000-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
de Feraudy, Sebastien; Ridd, Katie; Richards, Lauren M et al. (2010) The DNA damage-binding protein XPC is a frequent target for inactivation in squamous cell carcinomas. Am J Pathol 177:555-62
Cleaver, James E; Feeney, Luzviminda; Tang, Jean Y et al. (2007) Xeroderma pigmentosum group C in an isolated region of Guatemala. J Invest Dermatol 127:493-6
Laposa, Rebecca R; Feeney, Luzviminda; Crowley, Eileen et al. (2007) p53 suppression overwhelms DNA polymerase eta deficiency in determining the cellular UV DNA damage response. DNA Repair (Amst) 6:1794-804
Cleaver, J E; Hefner, E; Laposa, R R et al. (2007) Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair. Neuroscience 145:1300-8
de Feraudy, S; Limoli, C L; Giedzinski, E et al. (2007) Pol eta is required for DNA replication during nucleotide deprivation by hydroxyurea. Oncogene 26:5713-21
Laposa, R R; Huang, E J; Cleaver, J E (2007) Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice. Proc Natl Acad Sci U S A 104:1389-94
Marti, Thomas M; Hefner, Eli; Feeney, Luzviminda et al. (2006) H2AX phosphorylation within the G1 phase after UV irradiation depends on nucleotide excision repair and not DNA double-strand breaks. Proc Natl Acad Sci U S A 103:9891-6
Cleaver, James E (2005) Splitting hairs--discovery of a new DNA repair and transcription factor for the human disease trichothiodystrophy. DNA Repair (Amst) 4:285-7
Limoli, Charles L; Giedzinski, E; Cleaver, J E (2005) Alternative recombination pathways in UV-irradiated XP variant cells. Oncogene 24:3708-14
Wechsler, Thomas; Chen, Benjamin P C; Harper, Ryan et al. (2004) DNA-PKcs function regulated specifically by protein phosphatase 5. Proc Natl Acad Sci U S A 101:1247-52

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