The long term goal of this research program is to uncover and understand mutational pathways, the DNA repair processes that counteract these pathways, and the consequences of repair defects. This proposal is an extension of previous work that defined new """"""""mutator strains"""""""" in bacteria that have higher mutation rates than wild-type and that led to the elucidation of the GO system for oxidative damage. The human mutt gene, an essential component of this system, has been cloned. This work has now been extended to include targeted gene knockout mice. This proposal seeks to engineer and characterize a set of knockout mice lacking oxidative repair, as well as mice lacking different combinations of repair enzymes. Lacking certain repair systems can lead to cancer susceptibilities. It is therefore important to determine whether the absence of repair systems for oxidative damage leads to increased cancer rates or other abnormalities, such as accelerated aging. Specifically, the proposed research seeks to do the following. 1. Generate a double knockout mouse of mMYH with a DNA repair gene mOGG1. The OGG1 gene encodes a protein with a function similar to the bacterial MutM protein. Double knockouts might be expected to lack the ability to repair certain types of oxidative damage to the DNA. 2. Characterize mMYH knockout mice and mMYH-/- mOGG1-/- double knockout mice, analyze their phenotype and screen for abnormalities and cancer susceptibilities that might result from the reduced ability to repair oxidative damage. 3. Characterize primary mouse embryonic fibroblasts derived from both MYH-/- and MYH-/- OGG1-/- mice. 4. Generate and characterize additional combinations of mMYH knockout mice with other repair gene or tumor suppressor gene knockouts, such as MSH2 and p53.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA085952-01A1
Application #
6263004
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Pelroy, Richard
Project Start
2001-01-30
Project End
2004-12-31
Budget Start
2001-01-30
Budget End
2001-12-31
Support Year
1
Fiscal Year
2001
Total Cost
$306,000
Indirect Cost
Name
University of California Los Angeles
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Xie, Yali; Yang, Hanjing; Cunanan, Cristina et al. (2004) Deficiencies in mouse Myh and Ogg1 result in tumor predisposition and G to T mutations in codon 12 of the K-ras oncogene in lung tumors. Cancer Res 64:3096-102
Sieber, Oliver M; Howarth, Kimberley M; Thirlwell, Christina et al. (2004) Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (ApcMin/+) mice. Cancer Res 64:8876-81
Moran, Christopher J; Arenberg, Douglas A; Huang, Chiang-Ching et al. (2002) RANTES expression is a predictor of survival in stage I lung adenocarcinoma. Clin Cancer Res 8:3803-12