Neil Hunter: Understanding genomic instability
Cancers occur when genetic changes, or mutations, occur in genes that control normal cell activity. The mutations allow cells to grow and divide uncontrollably, ultimately leading to cancer. The rate at which mutations build up greatly increases when a cell’s own DNA repair mechanisms are defective.
“Every time a human cell divides it must engage these repair process. They are essential for the cell to survive,” said Neil Hunter, a UC Davis associate professor of microbiology. “The act of replicating a chromosome is fraught with difficulty. Aberrations of the replication and repair processes can lead to the kinds of chromosomal changes that cause cancer.”
When repair goes awry, chromosome segments can be deleted, duplicated and fused together in abnormal ways. These phenomena are collectively known as genomic instability and they make a cell more prone to harmful mutations.
Uncovering the secrets to DNA repair
Hunter and his colleagues are working to understand the nature and causes of this instability, the mechanisms of DNA repair and the consequences of defective DNA repair with respect to cancer.
“We’re trying to understand the molecular mechanisms behind the DNA repair process,” he said.
Hunter and his colleagues use baker’s yeast and mice as model organisms because the enzymes, or proteins, used in DNA repair have been highly conserved over evolutionary time — meaning they are virtually the same in yeast as in people. As the saying goes: DNA is DNA.
In the best-case scenario, cells accurately repair damaged chromosomes by using a second intact chromosome as a template. If the damaged DNA does not interact with its matching sequence on the template chromosome, there is a risk of rearrangement of chromosomes that can activate oncogenes, genes known to lead to cancer.
“Cancer cells are defective in basic processes that normally control cell growth,” Hunter said. Through genome instability, cancer cells acquire extra capacities to invade tissues and stimulate angiogenesis, or the growth of blood vessels, that feed a growing tumor.
Focusing on RecQ helicases
Hunter is working to describe the mechanisms behind a group of enzymes called DNA helicases. These proteins are responsible for unwinding the double-stranded DNA during repair. He is particularly focused on what are called RecQ-family DNA helicases.
Several syndromes that can lead to cancer have been directly linked to mutations in the genes that code for RecQ helicases, including:
Hunter, a native of England, earned his Ph.D. at Oxford University and did his postdoctoral work at Harvard University. It was during his graduate studies that the connection between cancer and faulty DNA repair became clear to him. During this time, researchers discovered that mutations in genes that repair DNA replication errors caused hereditary non-polyposis colon cancer.
The insights Hunter and his colleagues have made into the regulation of chromosome repair have given researchers a better understanding of the causes of cancer at a very basic level.
“This information will eventually help us pinpoint the weaknesses of tumor cells,” Hunter said. “Ultimately, this knowledge will allow us to improve the specificity of therapies and minimize unwanted side effects.”