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  • Writer's pictureAnnika B Von

Drosophila and DNA: Exploring Mechanisms of Double-Strand Break Repair

Many common cancer treatments, like chemotherapy or radiation, are not able to differentiate between healthy cells and cancerous cells reliably and accurately. Damaging healthy cells can cause extensive side effects for cancer patients undergoing treatment. As the Principal Investigator of the McVey Lab, Professor Mitch McVey's research into molecular mechanisms of DNA repair give way to possible therapies that allow for specific and targeted treatment of cancerous cells.


After graduating from the University of Colorado Boulder, Professor McVey taught high school students for two years with the Teach for America program. He earned his PhD at MIT and did a postdoctoral scholarship at the University of North Carolina Chapel Hill. As a graduate student, Professor McVey investigated the role of DNA repair and genome stability in aging. Following his passion for undergraduate teaching and research, Professor McVey came to Tufts, where he now teaches courses like Molecular Biology and Biology of Aging in the Tufts Department of Biology.


Professor McVey introduced three broad topics of investigation in the McVey lab. The lab uses Drosophila melanogaster, or the common fruit fly, as a model organism in their research. Because of the range of visible phenotypes and ease of genetic manipulation, the Drosophila system is ideal for biological research. The lab uses molecular tools like PCR to examine mechanisms of DNA repair in the flies.



Drosophila collage (image credit Anna Joseph)


The first area of research deals with DNA damage tolerance. Damaged DNA can impede the progress of DNA replication during the cell cycle, and the McVey lab is studying the proteins and pathways behind the ability of a cell to continue DNA replication despite damage.


The second area of research investigates a connection between bacteria with possible anti-inflammatory properties and the prevention of colon cancer. Using fruit flies to observe the effects of the bacteria, the McVey lab believes a protein on the surface of the bacteria triggers anti-inflammatory pathways within the guts and thus reduces chances of colon cancer.


The area of research that this article focuses on is DNA double-strand break repair. DNA double-strand breaks are often caused by exposure to DNA damaging agents such as radiation or toxic chemicals. The two phosphodiester backbones that provide support to the DNA double helix are broken, and "if a cell doesn't fix it, it's destined to die". Three distinct mechanisms exist to repair these double stranded breaks, the first of which is called homologous recombination. Genetic information similar to that missing at the broken region is copied off a template and used for repair, resulting in an accurate yet complicated break repair. Another mechanism is non-homologous end joining. Professor McVey refers to this method as the "duct tape repair pathway".   


"You basically take the ends, hold them in proximity to each other, and try and find a way to glue them back together."


Drosophila eye, in which double-strand break repair occurs (image credit Mitch McVey)


As a bit of genetic information can be lost in the process, it can be mutagenic (mutation-causing), yet mammalian cells prefer this method. The McVey lab focuses a third mechanism of double strand break repair called alternative end joining. The mechanism is similar to non-homologous end joining but uses an alternate pathway that has only recently begun to be explored and understood. As cancer cells frequently use alternative end joining, the lab is investigating which proteins are involved in the mechanism.


"Once you figure that out, you might be able to target those pathways, and potentially selectively kill cancer cells."


The lab has identified a protein crucial in alternative end joining called DNA polymerase theta, which promotes alternative end joining in almost all multicellular eukaryotic organisms. Cancer cells can regulate the expression of DNA polymerase theta, but as the protein is mutagenic, expression is harmful to cancer prevention efforts.


"It's not expressed at high levels unless you're a cancer cell or in certain situations where you're trying to deal with a lot of DNA damage in double stranded breaks."


Other labs have taken this information about DNA polymerase theta and developed small molecules that inhibit the protein for the purpose of treating cancer. Professor McVey shares his excitement about the potential therapeutics derived from this development that could be used to treat breast and ovarian cancers, for example. Focusing on DNA polymerase theta in combination with chemotherapeutic drugs and other treatments could prove especially effective in cancer treatments.


"You can target polymerase theta in those cancers, especially if you do combination therapy, for example with other chemotherapeutic drugs… The idea is that you start to combine these different therapies once you find out what genes are mutated in your cancer, and you might be able to target them specifically."


Despite the challenges of his research, Professor McVey affirms that "the moment of discovery in between the 30-50 failures every day is wonderful, that's what keeps you going." He encourages undergraduate students interested in research to get involved.


"As long as it's a lab where you think the questions are interesting, go for it."


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