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 o
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Contact: Steve Benowitz
steven.benowitz@mail.tju.edu
215-955-6300
Thomas Jefferson University
26-Dec-1997