December 4, 2000
By Holly Korschun
Emory 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 work were reported in the Nov. 15 issue of Cancer Research.
Paula Vertino, assistant professor of radiation oncology, and her colleagues
at the Winship Cancer Institute, 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
marked by methylation are normally turned off, or down-regulated; unmethylated
genes 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, Vertino said. While the DNA
sequence determines a genes 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.
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 (the 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.
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, Vertino
said. 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 responsible 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. 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 said. 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
Unlike a mutation, in which a gene is permanently damaged, methylation
is a reversible reaction. 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.