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Research suggests possible role of undermethylation in cancer

Scientists at MIT and the Whitehead Institute for Biomedical Research have established for the first time that DNA methylation, a chemical process by which cells alter how genes are read without changing the basic text, may also be responsible for maintaining the integrity of the genome, or in other words, for ensuring that the 3 billion-letter DNA code is copied accurately when cells divide.

The findings, reported in the September 3 issue of Nature, have implications for better understanding the molecular origins of cancer. These findings suggest that the early cancer cell may use reduced DNA methylation to decrease genome stability and increase the mutation rate, both of which are crucial for the development of malignant disease. The findings resolve contradictory results from previous research on the connection between methylation and cancer.

"One of the earliest hallmarks of cancer is the decreased stability of the cellular DNA, which causes genome rearrangements and mutations and sets the stage for the cell to develop malignant disease," says Professor of Biology Rudolf Jaenisch, a member of the Whitehead Institute and senior author on this study.

"Previously, some scientists found that tumor cells exhibited diminished methylation, while others have found excess methylation. Excess methylation was linked to the silencing of tumor suppressor genes, whereas the role of diminished DNA methylation in the malignant process was obscure," Professor Jaenisch said. "Our present study shows that reduced methylation may be responsible for the decrease in genomic stability, and therefore, the increase in mutations and chromosome loss seen in the early cancer cell."

In this study, first author Dr. Richard Chen and his colleagues in Professor Jaenisch's lab studied cultured mouse cells lacking DNA methyltrans-ferase (MTase), the enzyme responsible for methylating DNA. Mice carrying this mutation die in the womb. However, embryonic cells carrying the mutation can survive and grow in culture, providing researchers a useful system to study methylation.

The Whitehead researchers found that these embryonic cells have a mutation rate six to 10 times higher than normal, which suggests that there may be a causal relationship between reduced methylation and genome instability. Professor Jaenisch and colleagues found that the mutations in these cells take the form of deletions and seem to result from an increased rate of chromosomal recombination during cell division. These findings suggest that DNA methylation might ensure genome stability by ensuring that recombination doesn't take place during mitosis.

Scientists have linked changes in DNA methylation to the onset of cancer and aging as well as many critical aspects of gene regulation (e.g., genomic imprinting and X-inactivation). As a result, there has been widespread interest in deciphering the role of DNA methylation in the cancer research community.

The study was funded in part by grants from the Swedish Medical Research Council, the Ann Fuller Fund, the Damon Runyon-Walter Winchell Foundation and the National Institutes of Health.

A version of this article appeared in MIT Tech Talk on September 30, 1998.

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