Damage occurs to our genes every day, some of it due to chemical
or physical agents that have the potential to cause mutations
leading to cancer. Luckily, cell proteins detect such damage and
repair it before the cell reproduces, preventing a mutation. Scientists
have long suspected that defects in this repair process could
lead to an elevated risk of cancer. But until fairly recently,
specific DNA repair mechanisms were not well understood.
Two biochemists--Paul L. Modrich, phd, Professor of Biochemistry
and Investigator at the Howard Hughes Medical Institute at Duke
University Medical Center and Richard D. Kolodner, phd, Professor
of Biological Chemistry and Molecular Pharmacology at Harvard
Medical School and Chief of Human Cancer Genetics at the Dana
Farber Cancer Institute, unraveled the mystery of DNA "mismatch
repair" and its relationship to hereditary nonpolyposis colon
carcinoma (HNPCC). The most common cancer susceptibility syndrome,
HNPCC may affect as many as 1 in every 200 Americans, according
to some experts. DNA mismatch repair defects could now provide
"markers" of risk for HNPCC and the potential for treatments.
The pioneering work of Drs. Kolodner and Modrich over the past
14 years has been honored with the 1996 Charles S. Mott Prize
for Outstanding Research in Cancer Causation or Prevention, awarded
by the General Motors Cancer Research Foundation.
Elucidating the Genetic Repair System
It was in the 1980s that both researchers began their studies
of protein enzymes that help repair genetic damage.
Genes can be damaged either by mutagens or errors in replication,
resulting in damage, deletion, or mismatching of base pairs (twin
segments on the two strands of DNA that encode the function of
each gene). Changes in a base alter the function of a gene and
can result in the uncontrolled cell growth that forms tumors.
Normal genes contain proteins that detect discrepancies in genetic
information and correct DNA mismatches. When these enzymes are
defective or missing, the mismatched base pairs are copied each
time the cell reproduces, resulting in a genetic mutation that
can set the stage for disease. Although mutated genes that cause
disease are rapidly being discovered, without understanding the
defective mechanism within those genes, there's no way to develop
preventive or therapeutic strategies.
Dr. Modrich first focused his attention on mismatch repair activities
within Escherichia coli. In 1983 he discovered a set of
enzymes that repairs mismatches in this bacteria. After developing
biochemical assays, Dr. Modrich and colleagues were able to identify
10 proteins responsible for mismatch repair in E coli.
Then Dr. Modrich looked at human cells, and in 1990 discovered
a similar mismatch repair system, subsequently shown to depend
on proteins similar to the bacterial MutS and MutL.
"Whereas normal cells have a mismatch repair mechanism, hypermutable
cells, either bacterial or human, did not," remarks Dr. Modrich.
"The kind of mutations we identified were associated with
a variety of human tumors. We had also found a mismatch repair
defect in hypermutable human cell lines resistant to chemical
agents similar to those used in cancer."
"We have now purified proteins that can restore mismatch
repair function in vitro, which are virtually identical to bacterial
MutL or MutS. Three of those proteins encode for
the genes which carry defects identified in the HNPCC families,"
adds Dr. Modrich. "A fourth repair protein is associated
with a gene where defects have been frequently found in sporadic
cases of colon cancer, not associated with HNPCC families."
The Role of Humble Yeast
While Dr. Modrich was in pursuit of the mismatch repair proteins,
Dr. Kolodner was using model organisms like yeast to investigate
the repair enzymes and find the genes involved and their relationship
to human cancer susceptibility.
Based on the studies with E coli, Dr. Kolodner and colleagues
at Dana Farber developed in vitro assays for mismatch repair enzymes
in yeast cells. They also found equivalents to MutS, as
well as homologs to other bacterial repair enzymes.
Using information based on similarities in sequencing of yeast
and bacterial MutS and MutL proteins, his laboratory
and collaborators were able to isolate human DNA encoding for
corresponding genes. These genes were found to be located in the
same region as genes causing inherited forms of colon cancer.
A defect in the mismatch repair mechanism was simultaneously uncovered
in tumor cells removed from patients with HNPCC by Dr. Modrich's
group. Several other research teams found that the genetic mutation
in HNPCC involved defects in a protein similar to bacterial MutS.
In 1993, Dr. Kolodner and collaborators reported that mutations
in one mismatch repair gene, MSH2, predisposed people to HNPCC.
The following year, he and his collaborators reported that mutations
in a second mismatch repair gene, MLH1, also predisposed carriers
to colon cancer. Dr. Kolodner's laboratory has since cloned the
genomic regions encoding both genes and demonstrated that inherited
mutations in these genes cause HNPCC (also known as Lynch II syndrome).
So studies of the humble yeast cell, in part, have led to the
promise of genetic tests to identify individuals at risk for hereditary
colon cancer, who could be followed with heightened surveillance
to catch the cancer in its earlier, curable stages.
Similar defects in repair systems are likely associated with a
variety of sporadic cancers. "Lack of these repair enzymes
could potentially be markers for risk in other cancers as well,"
remarked Joseph G. Fortner, md, President of the General Motors
Cancer Research Foundation. And, he said, research into repair
enzymes could also aid in cancer diagnosis and development of
more effective treatments.
Lifetimes in the Lab
Dr. Kolodner received his undergraduate and graduate degrees in
biology and biochemistry from the University of California at
Irvine. After postdoctoral studies at Harvard Medical School (1975
to 1978), he came to Harvard Medical School and the Dana-Farber
Cancer Institute as an Assistant Professor of Biochemical Chemistry
in 1978. He became the Chair of the Charles A. Dana Division of
Human Cancer Genetics at Dana Farber in 1995.
Dr. Modrich received his bs in biology from Massachusetts Institute
of Technology and his phd in biochemistry from Stanford University
and pursued postdoctoral studies at Harvard from 1973 to 1974.
He joined the Duke University faculty in 1976 and was appointed
Investigator at the Howard Hughes Medical Institute there in 1994.