The last NIEHS Distinguished Lecture of 2016 featured a local scientist who is admired around the world for his research on how DNA corrects a particular type of error. Paul Modrich, Ph.D., James B. Duke Professor of Biochemistry at Duke University, specializes in DNA mismatch repair (MMR), a process that corrects mismatched base pairs that arise following DNA replication. His work earned him the 2015 Nobel Prize in Chemistry, along with Tomas Lindahl, Ph.D., M.D. and Aziz Sancar, M.D., Ph.D.
"The NIEHS Distinguished Lecture series is comprised of scientists who have garnered certain awards, such as membership in the National Academy of Sciences, being a Howard Hughes [Medical Institute] investigator, or a Nobel prize," said Bill Copeland, Ph.D., chief of the Genome Integrity and Structural Biology Laboratory, and one of three co-hosts for the event. "Today, we have the pleasure of someone with all three of those awards."
The other two NIEHS co-hosts, Matt Longley, Ph.D., and Leroy Worth Jr, Ph.D., were postdoctoral fellows in Modrich's group. They both expressed excitement about having their former advisor on campus. The Dec. 13 presentation was titled "Mechanisms in Human Mismatch Repair."
Human mismatch repair
Modrich said that MMR has several functions, including avoiding mutations by identifying and removing base pairing errors that differ from the usual A-T or C-G.
One of the most interesting features of the MMR pathway involves strand direction, which has to do with how DNA is structured. When the two strands of DNA are bound together to make a double helix, they run in opposite directions, also known as antiparallel. He said correction of DNA biosynthetic errors relies on secondary signals in the DNA helix to identify the new strand that contains a mistake.
Three proteins are involved in the initiation of human MMR, Modrich explained. MutS-alpha recognizes base-base mismatches and small insertion deletions 1-3 nucleotides in length, whereas MutS-beta recognizes small insertion deletions 2-10 nucleotides long. The cell must expend energy to recruit MutL-alpha to the DNA, but that protein can only bind if MutS-alpha and MutS-beta are already present. Assembly of these three-part complexes plays an important role in activating downstream repair events.
"When we began our work on human mismatch repair, we had no idea what the biological strand signals might be," Modrich said. "We had reason to believe, based on our work with E. coli MMR, that a DNA strand break might suffice [for activating downstream repair]."
His team then created circular DNAs with a nick or cut in either strand. By studying repair of these DNA molecules, Modrich’s team determined that bi-directional repair ability may operate in human MMR.
Additional work found that MMR has two, separate reactions. In the first, exonuclease 1, the protein responsible for cutting DNA nucleotides, is activated by MutS-alpha in a mismatch-dependent manner. In the second reaction, as Modrich has shown, MutL-alpha’s primary activity is to cleave bonds in the middle of the DNA chain. A portion of these studies were done in collaboration with NIEHS researcher Tom Kunkel, Ph.D.
Another finding built upon work performed by NIEHS scientist Dmitry Gordenin, Ph.D. Modrich said MutL-alpha is inhibited by cadmium, an environmental carcinogen implicated in lung and kidney cancer. In a 2003 Nature Genetics paper, Gordenin showed that the mutagenic action of cadmium is largely the result of selective inhibition of MMR.
Worth reflected on the totality of Modrich’s research. "The nice thing about this story is the importance of discovery-based research and how model systems can help us understand how living systems maintain the integrity of the genome and guard against both internal and external insults," he said.
Head and heart
Although Modrich’s scientific expertise makes him a global leader in the field of DNA repair, his down-to-earth personality allowed him to recruit exceptional postdocs and create an environment filled with learning and comradery. Longley reflected on his time in Modrich’s lab, by saying group members were like a large family, with Modrich playing the role of an easygoing patriarch.
"A lot of that was driven by Paul’s own personality, the warmth with which everyone interacted with one another," he said.