Source: iStock/© ktsimage
Source: iStock/© ktsimage

Certain parts of the genome that are especially vulnerable to damage nonetheless contribute to a crucial, “rubber meets the road” sort of functionality—molecular-level folding that maintains tertiary structures, regulates gene transcription, and attracts DNA-repair complexes. Oddly, points of failure happen to match points of heightened responsibility. Odder still, this seeming design flaw doesn’t appear to lead to as many genomic breakdowns, or “flats,” as it should. How does the genome keep rolling along? It’s not calling AAA.

According to scientists at the University of Utah and the University of Vermont, DNA contains an extra set of guanines, or G’s, that function like a spare tire. In fact, this spare can help the genome steer clear of cancer.

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 G’s. In order to stay cancer-free, our bodies must repair this DNA.

This is where the special vulnerability noted earlier comes in. It happens that the preferential oxidation of G’s threatens a regulatory structure called a G-quadruplex. When G’s of the G-quadruplex are oxidized, various structural changes occur. Unfortunately, these changes prevent the usual repair mechanism, base excision repair, from being carried out.

The Utah and Vermont researchers hypothesized that genome instability due to damaged G’s was somehow counteracted. They 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 G’s 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 G’s allowed the damages to fold out from the quadruplex structure, and become accessible to the repair enzymes.

These findings appeared July 6 in the journal ACS Central Science, in an article entitled, “A Role for the Fifth G-Track in G-Quadruplex Forming Oncogene Promoter Sequences during Oxidative Stress: Do These “Spare Tires” Have an Evolved Function?”

“[A] fifth G-track found a few nucleotides distant from the G4 tracks involved in folding can act as a ‘spare tire,’ facilitating extrusion of a damaged G-run into a large loop that then becomes a substrate for BER,” wrote the authors. “These new ‘spare tire’-containing strands with Gh [a G oxidation product] in loops are now found to be substrates for initiation of BER with the NEIL1, NEIL2, and NEIL3 DNA glycosylases.”

The authors asserted that their results support a hypothesis in which a fifth G-track aids in the repair process when vulnerable sequences are damaged by radical oxygen species. In addition, the authors noted that formation and repair of oxidized bases in promoter regions may constitute an additional example of epigenetic modification, in this case of guanine bases, to regulate gene expression in which the G4 sequences act as sensors of oxidative stress.








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