Project: Research project

Project Details


DESCRIPTION (Applicant?s Description): Altered DNA methylation patterns,
characterized by genome-wide hypomethylation in combination with CpG island
hypermethylation, are one of the most common features of human tumors. When a
promoter-associated CpG island becomes hypermethylated this can lead to
silencing of the gene in a heritable fashion. When this gene acts a key
regulator of cell growth then its silencing by improper de novo methylation
can lead to a growth advantage for the cell in a manner analogous to mutations
and deletions. In normal cells, CPG islands are kept unmethylated by
mechanisms which remain almost completely unknown. The objective of this
proposal is to gain a better understanding of the mechanisms which regulate de
novo methylation in normal cells and how dysregulation of these mechanisms
leads to improper CpG island hypermethylation. This will be achieved by the
accomplishment of three specific aims. The first will involve characterization
of the newly described putative de novo DNA methyltransferases (DNMTs) and a
determination of the effect on methylation patterns when these enzymes are
overexpressed or inhibited. In the second aim I will examine the role of
transcription factor binding and transcription in protecting DNA sequences
from de novo methylation. Lastly, a search will be carried out for proteins
which interact with the DNMTs using a two-hybrid system. The three aims of
this proposal will test the hypothesis that aberrant de novo methylation is a
consequence of two factors, (1) increased levels of one or more of the DNMTs
and (2) improper DNMT targeting or sequestration resulting from alterations in
proteins with which the DNMTs interact. Recent exciting findings related to
the role of DNA methylation in DNA repair, chromatin structure, and the
discovery of a new family of putative de novo DNMTs provides an excellent
starting point for this study and the successful accomplishment of these
specific aims should lead to a better understanding of how dysregulation of
the normal de novo methylation control mechanisms contributes directly to
StatusNot started


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