Nov. 21, 2000 Emory University scientists have discovered that a mistake in the way DNA is labeled and packaged could lead to the abnormal silencing of a gene that plays an important role in keeping breast cancer cells in check, thus contributing to cancer progression. Results of the research were reported in the Nov. 15 issue of Cancer Research.
Paula M. Vertino, Ph.D., and her colleagues at the Winship Cancer Institute of Emory University discovered that a gene called TMS-1, which is normally involved in apoptosis (programmed cell death), the process the body uses to help eliminate damaged or cancerous cells, is abnormally silenced by the overexpression of a particular type of enzyme that serves as a marker for DNA.
The enzymes, called methyltransferase enzymes, work as a marking crew for DNA by using a chemical reaction to transfer a methyl group onto the cytosine base regions of DNA molecules. Methylation serves as a flag for proteins that read and interpret the information contained in DNA. Genes that are marked by methylation are normally turned off, or down-regulated, and those that are unmethylated are expressed, or up-regulated.
"Methylation is a modification of DNA, and the pattern of which cytosine bases are methylated and which are not adds another level of information to the DNA sequence," Dr. Vertino explains. "While the DNA sequence determines a gene’s function, its pattern of methylation can dictate whether it is on or off."
In contrast to the DNA sequence, however, methylation is not built into the DNA and is not necessarily permanent. Methylation markers are not inherited in the same way as genetic sequences and genetic mutations, and they must constantly be replaced by methyltransferase enzymes. One variety of methyltransferase enzymes has the job of placing methylation markers on DNA during human development in the embryo; another variety of enzymes has the job of replacing the methylation markers each time a cell divides.
Dr. Vertino screened DNA to find genes that were down-regulated in response to aberrant methylation. She discovered that when a particular methyltransferase enzyme, called DNMT-1, is experimentally overexpressed, it mistakenly turns off the TMS-1 gene (target of methylation-induced silencing). She then found that the same gene was aberrantly methylated and silenced in human breast cancers. Since TMS-1 is a gene partly responsible for ridding the body of breast tumor cells through apoptosis, this silencing could lead to unrestricted tumor growth and progression of breast cancer.
Since most drugs and radiation used to treat human cancers work by inducing apoptosis, the silencing of a gene such as TMS-1 that promotes apoptosis could also lead to resistance to conventional cancer therapies.
Scientists have discovered other alterations in methylation patterns that are present in tumors, including undermethylation of places in the DNA that normally are methylated.
"We now know that abnormal increases in methylation can lead to aberrant silencing of important tumor suppressor genes," explains Dr. Vertino. "Loss of methylation groups also may contribute to tumor progression by causing chromosomes to become unstable, which can lead to genetic alterations. A major focus of our work is determining what is reponsible for this abnormal placement of methylation." In addition to DNMT-1, several other methyltransferase enzymes recently have been identified, but their exact roles and interactions with each other are not yet understood. Dr. Vertino also wants to clarify whether aberrant methylation is a cause or a consequence of tumorogenesis. She believes the answer will be a combination of the two.
"Some abnormal methylation events will cause silencing of a very important gene, or genes, and contribute directly to tumor formation," she reports. "And, some of the changes we see may be consequences of the fact that the tumor is genetically unstable. Aberrant methylation is propagated during cell division, just as a mutation in a DNA sequence would be."
Unlike a mutation, in which a gene is permanently damaged, methylation is a reversible reaction. Dr. Vertino has been able to reverse the silencing of TMS-1 using drugs that inhibit DNA methyltransferases, leading to re-expression of the gene. She hopes to accomplish the same thing in humans and thus re-establish growth control of tumor cells and sensitize resistant cells to chemotherapy or radiation.
One challenge to controlling aberrant gene silencing through drugs that inhibit methylation, will be devising a drug that is specific enough to demethylate certain genes without demethylating other parts of the genome that are supposed to be methylated. Results from the human genome project are helping Dr. Vertino study the controlling regions of regulatory genes such as TMS-1 to determine their exact methylation patterns.
Other Emory scientists also are studying methylation and its relationship to health and disease. Biochemist Xiadong Cheng, Ph.D. is working to crystallize the methyltransferase enzymes, with the goal of determining their precise functions and developing drugs that could control their interactions with DNA. He also is studying methylation that occurs in the protein products of gene expression. Pathologist Paul Wade, Ph.D., is studying the methylated DNA binding proteins that read and package the methylated DNA.
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