Grant: CIHR New Investigator

Normally, cells in the body grow, divide, and die in an orderly manner. Although there are many kinds of cancer, all develop when cells begin to divide abnormally. DNA is the material in every cell that directs all of its functions, the genetic blueprint of life. Tumor-suppressor genes are a subset of genes that encode the proteins that regulate cell growth. Mutation of the genes encoding these proteins leads to the development of cancer. In many cancer cells, these proteins are no longer produced, not because the genes that encode them have become mutated, but rather because the genes that encode them have been shut-off. This process frequently involves a specific chemical change in the DNA of these genes called methylation. Paradoxically, coincident with the methylation of tumor-suppressor genes, most of the genome in tumor cells, including vestigial "endogenous" viruses, becomes demethylated. The underlying cause of these alterations in DNA methylation patterns remains a mystery. The aim of this proposal is to characterize the underlying mechanism(s)/biochemical pathway(s) leading to DNA methylation of the genome in normal cells, using the mouse as a model system. Knowledge gained from this work may lead to the development of pharmaceuticals that counteract or inhibit aberrant DNA methylation observed not only in cancer, but in other diseases as well, such as Fragile X, ICF and ATRX syndromes.