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April 14, 2016

How a miniscule worm is helping scientists kick cancer

There are hundreds of genetic contributors to cancer, but one of the most notorious is tumour suppressor p53 — the most frequently mutated gene in human cancer. If you have a mutation in this gene, it is almost certain that other genetic changes will occur that transform a normal cell into a cancer cell. Although p53 has been known for many years to protect cells from getting mutations, scientists did not have a good understanding of how it functioned to help repair the damaged DNA until now.

In a new study led by The Hospital for Sick Children (SickKids), researchers used a miniscule nematode worm called C. elegans to uncover the gene’s function. They found that p53 in this organism plays a key role in deciding to repair damaged DNA in a precise and error-free manner.

“When p53 is mutated an error-prone method of repairing DNA is unleashed, which leads to a build-up of mutations that can ultimately drive the cells to a cancer state,” says Dr. Brent Derry, Principal Investigator of the study and Senior Scientist in Developmental & Stem Cell Biology at SickKids. “Previous research has primarily focused on how p53 destroys cells, or stops them from dividing, but this new work shines light on how it functions to repair DNA. Our findings are exciting because what we’ve learned here provides new insights into how p53 ensures genome stability that we can now pursue in human cells.”  

To accomplish this, Derry and his student Abigail Mateo, lead author of the study, are collaborating with SickKids scientist Dr. David Malkin, who specializes in a genetic cancer predisposition disorder called Li Fraumeni syndrome.  Patients with Li Fraumeni syndrome have a very high incidence of cancer because they inherit mutations in the p53 gene from one of their parents. Derry and Malkin plan to explore the significance of these findings in tumour cells from Li-Fraumeni patients.

“The mechanisms by which cells repair their DNA in worms is not much different from how it is accomplished in humans. Worms have very similar genes and proteins as humans, and they function in pretty much the same way. Many fundamental discoveries made in this organism have made a significant impact on human biology, and provided us with enormous amount of insight into human diseases like cancer,” adds Derry, who is also Associate Professor in the Department of Molecular Genetics at the University of Toronto.  

Abigail Mateo is a graduate student in the Department of Molecular Genetics at the University of Toronto and a trainee in Developmental & Stem Cell Biology at SickKids. This work was done in collaboration with Dr. Judith Yanowitz at Magee-Womens Research Institute in Pittsburgh, Pennsylvania. For more in-depth information about this research, please read the study in the April 14 online edition of Current Biology.

This research was supported by a grant from the Garron Family Cancer Centre at SickKids, the Canadian Institutes for Health Research, the National Institutes of Health, and Magee-Womens Research Institute startup funds.