Abstract

This project proposes the continuation of studies on the molecular pathology of human hereditary diseases which are characterized by defects in the cellular processing of damaged DNA, and their relationship to cancer. The recent observation that the human ERCC2 gene corrects the repair-defective phenotype of cells from individuals with xeroderma pigmentosum (XP) complementation group D, will be investigated further. XP-D cells, including cells from XP-D individuals with the associated disease trichothiodystrophy (TTD), will be investigated for the presence of mutations in XP-D alleles and mutations will be mapped and characterized. The cloned ERCC2 gene will be overexpressed and its protein product will be purified and characterized in detail. Gene replacement experiments will be carried out in mouse embryonic stem (ES) cells by homologous recombination with the genomic mutated mouse ERCC2 gene. These cells will be injected into blastocysts which will be brought to gestational maturity in pseudopregnant mice. Recombinant heterozygous mice will be bred to generate homozygous mutant strains carrying defects in the ERCC2 gene. The mice will be used to study the pathobiology of defective DNA repair under controlled environments and in the presence of known carcinogens. A recently developed Epstein Barr virus (EBV)-based episomal cloning vector will be used to screen human cDNA libraries for genes which complement the UV sensitivity of XP cells from genetic complementation groups C, F, G and V(variant), as well as cells from Cockayne's syndrome (CS) from genetic complementation group A.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA044247-12
Application #
2330739
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1987-02-01
Project End
1998-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
12
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

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

  Publications

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

Showing the most recent 10 out of 35 publications