The long-term objectives of this proposal are to investigate the relationship of defective repair of DNA damage to cancer in humans. To this end mutational inactivation of various DNA repair genes in mice by targeted gene replacement is being used as an experimental strategy. A mouse strain has been generated which carries homozygous deletions in the nucleotide excision repair (NER) gene XPC. This strain is exceptionally prone to ultraviolet (UV) radiation-induced skin cancer. Experiments are in progress to determine predisposition to liver cancer associated with exposure to the liver carcinogen 2-acetylaminofluorene, the repair of which requires the process of NER in mammals. XPC-1- mice that are additionally heterozygously or homozygously defective in the p53 tumor suppresser gene exhibit an even greater predisposition of skin cancer. Studies are proposed to investigate the mechanism of this synergistic interaction, in particular whether abrogation of the G1->S checkpoint function or of the apoptotic function of the p53 gene (or both), mediates this effect. Dr. Friedberg will generate a mouse strain by targeted gene replacement that is homozygous defective in the HAP1 gene which encodes the major apurinic/apyrimidinic (AP) endonuclease required for the process of base excision repair (BER) in mice. Such a mutant mouse is expected to be defective in the repair of various types of spontaneous base damage in DNA, particularly that generated by oxidative metabolism. Crosses will be made between the XPC-1- (NER-defective) mouse, the HAP1-/- (BER-defective) mouse and mice defective in the mismatch repair defective mouse MSH2, in order to investigate the role of all three known excision repair pathways in both spontaneous and environmental carcinogen-induced cancer in mammals.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA044247-14
Application #
2871718
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Okano, Paul
Project Start
1987-02-01
Project End
2003-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
14
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Meira, Lisiane B; Cheo, David L; Reis, Antonio M et al. (2002) Mice defective in the mismatch repair gene Msh2 show increased predisposition to UVB radiation-induced skin cancer. DNA Repair (Amst) 1:929-34
Fischhaber, Paula L; Gerlach, Valerie L; Feaver, William J et al. (2002) Human DNA polymerase kappa bypasses and extends beyond thymine glycols during translesion synthesis in vitro, preferentially incorporating correct nucleotides. J Biol Chem 277:37604-11
van der Horst, Gijsbertus T J; Meira, Lisiane; Gorgels, Theo G M F et al. (2002) UVB radiation-induced cancer predisposition in Cockayne syndrome group A (Csa) mutant mice. DNA Repair (Amst) 1:143-57
Meira, L B; Devaraj, S; Kisby, G E et al. (2001) Heterozygosity for the mouse Apex gene results in phenotypes associated with oxidative stress. Cancer Res 61:5552-7
Mullenders, L H; Berneburg, M (2001) Photoimmunology and nucleotide excision repair: impact of transcription coupled and global genome excision repair. J Photochem Photobiol B 65:97-100
Queimado, L; Rao, M; Schultz, R A et al. (2001) Cloning the human and mouse MMS19 genes and functional complementation of a yeast mms19 deletion mutant. Nucleic Acids Res 29:1884-91
Meira, L B; Reis, A M; Cheo, D L et al. (2001) Cancer predisposition in mutant mice defective in multiple genetic pathways: uncovering important genetic interactions. Mutat Res 477:51-8
Friedberg, E C; Bond, J P; Burns, D K et al. (2000) Defective nucleotide excision repair in xpc mutant mice and its association with cancer predisposition. Mutat Res 459:99-108
Cheo, D L; Meira, L B; Burns, D K et al. (2000) Ultraviolet B radiation-induced skin cancer in mice defective in the Xpc, Trp53, and Apex (HAP1) genes: genotype-specific effects on cancer predisposition and pathology of tumors. Cancer Res 60:1580-4
van Oosten, M; Rebel, H; Friedberg, E C et al. (2000) Differential role of transcription-coupled repair in UVB-induced G2 arrest and apoptosis in mouse epidermis. Proc Natl Acad Sci U S A 97:11268-73

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