The overall objective of this research proposal is to understand the mechanism by which epigenetic processes such as DNA methylation can contribute to neoplasia. We wish to investigate a direct causal role for DNMT1, the major mammalian maintenance DNA (cytosine-5) methyltransferase, in inducing C-T transition mutations similar to that shown for bacterial (cytosine-5) methyltransferases. This will involve the creation of conditional and tissue-specific alleles of DNMT 1 and the generation of transgenic mice and primary murine embryonic fibroblast (MEFs) cell lines using the established Cre/LoxP or Flp/Frt system and standard genetic methods. We will define the role of Dnmt1 in the incidence of point mutations in MEFs harboring the various conditional alleles by performing a quantitative analysis that measures spontaneous and induced mutation frequencies. We will then analyze wild-type and tumor prone mice that contain tissue-specific and conditional alleles of DNMT1 for the incidence of genomic methylation, incidence of point mutations, and tumor formation. These studies may provide a novel paradigm for understanding events that lead to abnormal cellular proliferation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA094664-03
Application #
6906347
Study Section
Special Emphasis Panel (ZRG1-F09 (20))
Program Officer
Lohrey, Nancy
Project Start
2002-08-01
Project End
2005-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$48,928
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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