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Rendering of a double-stranded DNA break
We all know DNA to be the most crucial molecule in living things—it’s what makes us unique individuals. But what happens when this vital structure is struck with damaging radiation? Or when it is altered as a result of the aging process? DNA damage can have serious consequences, which is why cellular mechanisms in place to repair this damage are so vital to the survival and functionality of organisms.
Dr. Mitch McVey is a Professor in the Tufts Department of Biology and the Principal Investigator of the McVey Lab, which uses the model organism Drosophila melanogaster (fruit flies) to study DNA repair mechanisms, particularly for double-stranded breaks. These double stranded breaks may occur from certain exposures (i.e. harmful radiation) as well as the movement of transposable elements (also called transposons), which are essentially DNA sequences that move throughout the genome. Another major research focus of the McVey Lab is mechanisms for tolerating DNA damage encountered while the cell is actively dividing and DNA is being replicated.
When a cell is in this position and the replication fork (the “unzipped” part of a DNA molecule being replicated) is blocked by a double-stranded break, it has to make a choice. According to Professor McVey, cells can either “bypass the lesions [and] try to keep replicating by making mistakes in the process” or “use more complicated mechanisms that take longer but tend to bypass the damage with fewer mistakes.” This decision happens almost instantaneously, as with most cellular processes, but is not always predictable.
Generally speaking, at least in the model organisms in the McVey Lab, the damage-tolerating cell prefers to take the error-prone pathway that bypasses the molecular break. Ultimately, the reasoning for this tendency is about speed. These cells are actively replicating their DNA for division, which is an incredibly fast process, and are willing to risk potential errors or further damage if it means they are able to replicate their DNA more efficiently, since in that moment their main purpose is to divide. However, the trade off for speed is that more often than not, this mechanism leads to mutations. This then begs the question: what would happen to the fruit fly if this damage tolerance strategy created significant errors in the cell’s DNA sequence?
Unfortunately, the answer is pretty anticlimactic—not much. While these mutations will likely alter cell function to an extent, they are not enough to end up killing the organism. Additionally, future offspring of a particular Drosophila with mutations caused by this pathway would not be affected whatsoever. Since these actively dividing cells are somatic cells (the body cells of functioning adult fruit flies), any mistakes or mutations created would not be passed on to offspring, because gametes used for reproduction are produced using an entirely different cell division pathway. Since there are no evolutionary or fitness consequences for the fruit fly, it makes biological sense as to why McVey Lab has observed that the error-prone pathway is preferred for tolerating DNA damage.
An interesting connection made by Professor McVey is that there seem to be some similarities in the behavior of somatic cells observed in Drosophila and cancerous cells. When cancer cells, who replicate their DNA at an even faster rate, encounter damage during DNA replication, they also prefer the error-prone method.
Professor McVey also discussed how the genome instability that results from DNA damage and repair can also offer some insights into the complicated field of aging, since organisms cannot perfectly maintain their tissues over time, especially as consequences of somatic cell mutation add up. According to Professor McVey, these findings are merely “one piece of the puzzle in regards to what aging is [and] why organisms age.”
Finally, Professor McVey was able to talk more broadly about the field, and how it has adapted to a world in which research cannot operate in its usual fashion.
When asked to give advice to undergraduates looking for research positions amid various COVID-related lab restrictions, Professor McVey said: “Don't be dissuaded and try to think of creative ways that you can get involved in the research process, even though you may not physically be in a lab. For example, if there are labs that you're interested in, see if you can attend the [virtual] lab meetings to start to get a handle on what research actually is in those labs. When the time comes and you can physically be in the labs, you'll be that much further ahead with the process.”
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