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
Damage occurs to our genes every day, some of it due to chemicalor physical agents that have the potential to cause mutationsleading to cancer. Luckily, cell proteins detect such damage andrepair it before the cell reproduces, preventing a mutation. Scientistshave long suspected that defects in this repair process couldlead 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 Biochemistryand Investigator at the Howard Hughes Medical Institute at DukeUniversity Medical Center and Richard D. Kolodner, phd, Professorof Biological Chemistry and Molecular Pharmacology at HarvardMedical School and Chief of Human Cancer Genetics at the DanaFarber Cancer Institute, unraveled the mystery of DNA "mismatchrepair" and its relationship to hereditary nonpolyposis coloncarcinoma (HNPCC). The most common cancer susceptibility syndrome,HNPCC may affect as many as 1 in every 200 Americans, accordingto 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 past14 years has been honored with the 1996 Charles S. Mott Prizefor Outstanding Research in Cancer Causation or Prevention, awardedby the General Motors Cancer Research Foundation.
Elucidating the Genetic Repair System
It was in the 1980s that both researchers began their studiesof 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 (twinsegments on the two strands of DNA that encode the function ofeach gene). Changes in a base alter the function of a gene andcan result in the uncontrolled cell growth that forms tumors.Normal genes contain proteins that detect discrepancies in geneticinformation and correct DNA mismatches. When these enzymes aredefective or missing, the mismatched base pairs are copied eachtime the cell reproduces, resulting in a genetic mutation thatcan set the stage for disease. Although mutated genes that causedisease are rapidly being discovered, without understanding thedefective mechanism within those genes, there's no way to developpreventive or therapeutic strategies.
Dr. Modrich first focused his attention on mismatch repair activitieswithin Escherichia coli. In 1983 he discovered a set ofenzymes that repairs mismatches in this bacteria. After developingbiochemical assays, Dr. Modrich and colleagues were able to identify10 proteins responsible for mismatch repair in E coli.Then Dr. Modrich looked at human cells, and in 1990 discovereda similar mismatch repair system, subsequently shown to dependon proteins similar to the bacterial MutS and MutL.
"Whereas normal cells have a mismatch repair mechanism, hypermutablecells, either bacterial or human, did not," remarks Dr. Modrich."The kind of mutations we identified were associated witha variety of human tumors. We had also found a mismatch repairdefect in hypermutable human cell lines resistant to chemicalagents similar to those used in cancer."
"We have now purified proteins that can restore mismatchrepair function in vitro, which are virtually identical to bacterialMutL or MutS. Three of those proteins encode forthe genes which carry defects identified in the HNPCC families,"adds Dr. Modrich. "A fourth repair protein is associatedwith a gene where defects have been frequently found in sporadiccases 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 investigatethe repair enzymes and find the genes involved and their relationshipto human cancer susceptibility.
Based on the studies with E coli, Dr. Kolodner and colleaguesat Dana Farber developed in vitro assays for mismatch repair enzymesin yeast cells. They also found equivalents to MutS, aswell as homologs to other bacterial repair enzymes.
Using information based on similarities in sequencing of yeastand bacterial MutS and MutL proteins, his laboratoryand collaborators were able to isolate human DNA encoding forcorresponding genes. These genes were found to be located in thesame region as genes causing inherited forms of colon cancer.
A defect in the mismatch repair mechanism was simultaneously uncoveredin tumor cells removed from patients with HNPCC by Dr. Modrich'sgroup. Several other research teams found that the genetic mutationin HNPCC involved defects in a protein similar to bacterial MutS.
In 1993, Dr. Kolodner and collaborators reported that mutationsin one mismatch repair gene, MSH2, predisposed people to HNPCC.The following year, he and his collaborators reported that mutationsin a second mismatch repair gene, MLH1, also predisposed carriersto colon cancer. Dr. Kolodner's laboratory has since cloned thegenomic regions encoding both genes and demonstrated that inheritedmutations in these genes cause HNPCC (also known as Lynch II syndrome).
So studies of the humble yeast cell, in part, have led to thepromise of genetic tests to identify individuals at risk for hereditarycolon cancer, who could be followed with heightened surveillanceto catch the cancer in its earlier, curable stages.
Similar defects in repair systems are likely associated with avariety of sporadic cancers. "Lack of these repair enzymescould potentially be markers for risk in other cancers as well,"remarked Joseph G. Fortner, md, President of the General MotorsCancer Research Foundation. And, he said, research into repairenzymes could also aid in cancer diagnosis and development ofmore effective treatments.
Lifetimes in the Lab
Dr. Kolodner received his undergraduate and graduate degrees inbiology and biochemistry from the University of California atIrvine. After postdoctoral studies at Harvard Medical School (1975to 1978), he came to Harvard Medical School and the Dana-FarberCancer Institute as an Assistant Professor of Biochemical Chemistryin 1978. He became the Chair of the Charles A. Dana Division ofHuman Cancer Genetics at Dana Farber in 1995.
Dr. Modrich received his bs in biology from Massachusetts Instituteof Technology and his phd in biochemistry from Stanford Universityand pursued postdoctoral studies at Harvard from 1973 to 1974.He joined the Duke University faculty in 1976 and was appointedInvestigator at the Howard Hughes Medical Institute there in 1994.