A Master of Mutations
Goodman investigates origins of genetic change
By Eva Emerson
In the world of biology, mutations—changes in the genetic material of a living cell—can kill. In response, living things, from bacteria to human cells, have evolved extensive cellular machinery to guard the integrity of their genomes.
That has made the discovery of how cells actively introduce mutations in DNA all the more surprising, says USC molecular biologist Myron F. Goodman, who investigates the biochemical origins of gene mutations.
“Overwhelmingly, DNA mutations are bad for cells,” says Goodman, professor of biological sciences and chemistry at USC College. “Yet, in some situations, there are advantages of having a system that introduces mutations.”
Recent research by Goodman suggests how the risks of genetic change are balanced by its potential benefits. In a study published in the June 11, 2002 issue of Proceedings of the National Academy of Sciences (PNAS), Goodman and Steve Finkel, assistant professor of molecular biology, show that bacteria with genes associated with mutation can out-compete bacteria lacking the genes.
“The exciting thing is that the cell requires this system for fitness, that the genes provide a selective advantage,” Goodman says. “Remarkably, they seem to be there to deliberately introduce mutations.”
Mutations, the reasoning goes, introduce genetic diversity within a population of bacteria, allowing for rapid adaptation. In bacteria, one cell with an advantageous mutation can quickly repopulate the entire colony.
Chief of the division of molecular and computational biology in the biology department, Goodman has long studied the molecular systems that read and copy DNA in the bacteria E. coli. In the process, he has made fundamental contributions to the understanding of both normal and aberrant DNA replication and repair, and the origins of genetic change.
His discoveries have provided insight into a host of biological processes ranging from cell mutation to evolution, as well as clinical problems including genetic diseases, aging and cancer.
Goodman began his career in electrical engineering, earning a Ph.D. from Johns Hopkins University in 1968. His graduate work in theoretical quantum electronics gradually drifted toward biology. His thesis looked at laser interactions with biological molecules. That led to a five-year fellowship in the biochemistry lab of Maurice Bessman at Johns Hopkins and, in 1973, to a job offer from USC. “I’ve never regretted turning my focus to biology,” he says.
Goodman first received widespread recognition when he developed the technique used to measure the accuracy of the enzymes that copy DNA, revealing the incredible fidelity of DNA replication under normal conditions. Mistakes that could lead to mutation occur rarely, he showed, at a rate of one in 10,000 to 1,000,000 DNA bases incorporated into a new strand. The assay he developed remains widely used today.
Goodman’s search for the molecular roots of mutation next led him to look at what happens in cells damaged by ultraviolet light. Since the early 20th century, scientists had known that X-ray and ultraviolet (UV) radiation, as well as certain toxic chemicals, can kill cells and leave survivors replete with genetic mutations. So, 30 years ago, it surprised scientists when they discovered a strain of bacteria that, unlike normal strains, did not develop mutations when exposed to UV light.
The finding suggested something wholly unexpected: While UV exposure did damage DNA, it did not cause mutations directly, as had been thought. Instead, UV damage appeared to trigger an emergency response, later called SOS, which somehow actively introduced mutations in the cells that survived.
Goodman has helped to unravel the molecular details of the SOS response, which also is called SOS mutagenesis. The SOS response involves more than 40 genes, Goodman says, many of which produce enzymes that act immediately to repair damage. Goodman’s team was the first to reveal the role of one of these enzymes, DNA polymerase II, in DNA damage control.
In 1998, Goodman made a major discovery—his team identified a new SOS DNA-copying enzyme, called DNA polymerase V (pol V), unique in that it acts 45 minutes after UV exposure.
Notably, pol V can copy DNA even when confronted with heavily damaged sections of DNA strands. When normal polymerases come to these areas, which Goodman refers to as train wrecks, DNA copying is halted. But pol V can take over and copy these damaged sections, which allows the cell to continue to grow and divide. This ability is balanced by the enzyme’s low fidelity—it incorporates the wrong DNA base about once in 100 to 1,000 bases, earning pol V the name “sloppier copier.”
Goodman’s discovery of pol V launched a new area of research as scientists searched for related polymerases in other organisms. Prior to 1998, just five DNA polymerases were known in eukaryotes, which includes yeast and human cells. Since then, the number has jumped to 15 and counting, including enzymes found in human cells.
Goodman and Finkel’s work suggests an advantage to cells of the sloppy copying of the pol V enzyme—it appears to help bacterial cells adapt in unfavorable conditions. In other papers published in the summer of 2002, Goodman’s team revealed more about the biochemistry of pol V, including the details of how a common cell protein, Rec A, facilitates the process.
Goodman, who currently leads four grant-funded projects, also studies programmed mutation in the human immune system. Low-fidelity human enzymes similar to pol V appear to copy DNA in antibody-producing B cells, resulting in the generation of the diverse antibodies needed to fend off attacks from an enormous variety of disease-causing agents.
In human genetics, Goodman and John Petruska, professor of biology, investigate the DNA polymerase-based mechanisms involved in the expansion of repeated three-letter sections of DNA, called trinucleotide repeats, a motif shown to cause many serious neurological diseases including Huntington’s diesase and Fragile X Syndrome.
In 2000, Goodman received a prestigious MERIT award from the National Institutes of Health (NIH). MERIT (Method to Extend Research in Time) awards are bestowed on fewer than 5 percent of all NIH grantees each year. All told, the 10-year grant provides more than $2 million in research funding for Goodman’s lab. Among many other awards, he also has been honored with the 2001 USC Associates Award for Creativity in Research and Scholarship.
“Myron Goodman’s work on this new class of enzymes represents a major breakthrough in our fundamental knowledge of biology,” says Joseph Aoun, dean of the College. “It also suggests possible applications in clinical medicine and gives us a new appreciation of how living things get the raw materials needed for evolutionary change.”
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