Carrying around a spare tire is a good thing -- you never know when you'll get a flat. Turns out we're all carrying around "spare tires" in our genomes, too. Today, in ACS Central Science, researchers report that an extra set of guanines (or "G"s) in our DNA may function just like a "spare" to help prevent many cancers from developing.
Various kinds of damage can happen to DNA, making it unstable, which is a hallmark of cancer. One common way that our genetic material can be harmed is from a phenomenon called oxidative stress. When our bodies process certain chemicals or even by simply breathing, one of the products is a form of oxygen that can acutely damage DNA bases, predominantly the Gs. In order to stay cancer-free, our bodies must repair this DNA. Interestingly, where it counts -- in a regulatory DNA structure called a G-quadruplex -- the damaged G is not repaired via the typical repair mechanisms. However, people somehow do not develop cancers at the high rate that these insults occur. Cynthia Burrows, Susan Wallace and colleagues sought to unravel this conundrum.
The researchers scanned the sequences of known human oncogenes associated with cancer, and found that many contain the four G-stretches necessary for quadruplex formation and a fifth G-stretch one or more bases downstream. The team showed that these extra Gs could act like a "spare tire," getting swapped in as needed to allow damage removal by the typical repair machinery. When they exposed these quadruplex-forming sequences to oxidative stress in vitro, a series of different tests indicated that the extra Gs allowed the damages to fold out from the quadruplex structure, and become accessible to the repair enzymes. They further point out that G-quadruplexes are highly conserved in many genomes, indicating that this could be a factory-installed safety feature across many forms of life.
Due to a premature posting of this paper online, the embargo is now lifted as of July 6.
The authors acknowledge funding from the National Institutes of Health.
The paper will be available July 8, 2015, at this link: http://pubs.
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