Dec. 30, 1997 When mismatch repair genes go awry, the result may be colon cancer. Such genes are part of the intricate molecular machinery that fixes the cell when for some reason, cell replication doesn’t work correctly.
Now, molecular geneticist Richard Fishel, Ph.D., professor of microbiology and immunology, along with colleagues Scott Gradia and Samir Acharya, Ph.D., at the Kimmel Cancer Center and Jefferson Medical College of Thomas Jefferson University in Philadelphia have uncovered a new molecular switch by which mismatch repair is triggered. The work has the potential to enable researchers to specifically target anticancer drugs to these genes.
According to Dr. Fishel, who was a co-discoverer of the hMSH2 and hMLH1 colon cancer tumor suppressor genes, only two genes--MSH2 and MLH1--are altered frequently in Hereditary Nonpolyposis Colorectal Cancer, which accounts for some 10 to 15 percent of all colorectal cancers. “We’d like to know why alterations in only two of the five known mismatch repair genes cause cancer,” he says. [The other mismatch repair genes are hMSH3, hMSH6 and hPMS2. They function as protein complexes: hMSH2-hMSH3, hMSH2-hMSH6 and hMLH1-hPMS2]
Dr. Fishel and his co-workers have identified the function of two of those key genes in the mismatch repair complex--hMSH2-hMSH6. “Scientists had been trying to understand the real function of these genes since their discovery,” Dr. Fishel says. [Now we know that] “they serve as a regulatory molecular switch. Because we understand the true function, we are provided with a foundation to target the process as a whole.”
Dr. Fishel and his colleagues report their results in the December 26 issue of the journal Cell.
According to Dr. Fishel, a mismatch of the DNA nucleotides, or building blocks, may occur during cell replication. In replication, precise nucleotide pairing is essential. Researchers have known that in bacteria a protein, MutS, recognizes a replication error and binds to the mismatched nucleotides. In human cells it is the hMSH2-hMSH6 protein complex that attaches to the mismatched nucleotides. Other proteins, such as the bacterial MutL (or in humans, hMLH1-hPMS2), are involved in relaying these mismatch recognition signals. This occurs by assembling the repair machinery which then orchestrates the correction of these errors. “Without hMSH2 or hMLH1 the cellular DNA becomes unstable [genome instability], errors accumulate and the result is cancer,” Dr. Fishel explained.
In their experiments, the scientists measured the initial binding of hMSH2-hMSH6 to a mismatch of the nucleotides G (guanine) and T (thymine) in the DNA. Normally, G (guanine) pairs with C (cytosine) and T (thymine) pairs with A (adenine). A G-T pair is a mismatch.
Dr. Fishel notes that their results support a new model to explain the triggering of the mismatch repair mechanism. This is based on the association--or disassociation--of the protein complex, hMSH2-hMSH6, from the mismatched nucleotides. The scientists found that the molecular switch is “off” when a molecule of ATP--adenine triphosphate--is attached to the complex. When a phosphate molecule is removed, leaving ADP--adenine diphosphate--the switch is “on” and bound to the mismatch.
Dr. Fishel believes that the correct assembly of the repair machinery allows the switch to function properly. “hMSH2-hMSH6 binds [to the mismatched nucleotide pair] and once this whole complex is assembled, it flicks the switch,” he says.
According to Dr. Fishel, “these switches and regulators” may be targets for future anticancer drugs.
“Any cellular manipulation of its DNA is an inherently risky process since loss or alterations can result in mutations or cell death,” Dr. Fishel says. “To accurately perform such processes, it is likely that the cell assembles all of the necessary components. Then a switch initiates the actual event. What we’ve found is one of those switches, and that’s the novelty". According to Fishel, this is the first identification of such a switch in DNA metabolism.
“This a real basic science finding, and it will change the way we think about DNA metabolic events,” he contends. “It has profound implications regarding other DNA processes. From a cancer standpoint, there is clear genomic instability in most tumors,” he says. “Yet we don’t find mutations in the mismatch repair genes in all of these cancers.” Fishel believes that similar regulatory switches may be involved in these other cancers. "Now that we understand one of these switches, we can look for similar switches in other cellular DNA processes and their role in the development of cancer".
According to the American Cancer Society, colon and rectal cancer is the third most common cancer in the nation, with some 200,000 new cases diagnosed annually.
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