Nucleic Acid Story

New Research Shows Another Reason DNA is the Genetic Datakeeper for Life
August 12, 2016

DNA has been the primary librarian of genetic information for billions of years. Four chemical bases, lined up and repeated 3.2 billion times and twisted into the famous “double helix,” have steered the growth, reproduction and evolution of life on Earth since the dawn of the cell. Its code of repeated A,T,C and G bases is so elegant and its chemistry is so stable that software companies even want to use it as an ultra-compact data storage.

DNAIt can be easy to forget that DNA most likely was not the first genetic molecule. According to popular theories on the origin of life, DNA’s older brother, RNA, built itself from the steaming pits of early Earth’s primordial sludge, opened the business of making proteins—a job RNA still monopolizes today—and even learned to replicate itself to keep life going in the right direction.

Then DNA swooped in with its fancy, stable backbone and its two corkscrewed strands like Buzz Lightyear with his jetpack and has been life’s favorite toy ever since.

Unfortunately for RNA, the Woody of this story, DNA’s dominance of the toy chest does not appear to be waning any time soon. In fact, new research from Duke University has found a feature of DNA that makes it more flexible, versatile and durable compared to RNA.

Duke biochemist Hashim Al-Hashimi, discovered that the individual bases that make up the DNA strand can spontaneously flip and attach to each other upside down, which allows the actual double helix to change its shape and put in a quick repair when the DNA gets damaged while RNA cannot.

He published the research in the journal Nature Structural and Molecular Biology.

To understand the importance of what is in reality a miniscule change in the structure of a gigantic molecule, you need to know a little bit about how DNA is built.

RNAEach base on the DNA strand has three pieces: a deoxyribose sugar molecule—hence the “D” in DNA—a phosphate molecule and a nitrogen base. If you have ever seen a picture of a DNA molecule that looks like a twisted ladder, the sugar and phosphate make up the sides of the ladder and they always stay the same, while the nitrogen bases make up the rungs, and vary to give each base its A, T, C or G identity. RNA is the same except it has a ribose sugar—hence the R—and a U instead of a T.

The nitrogen bases on each strand connect to each other with weak chemical bonds called hydrogen bonds—A bonds to T, C bonds to G. For years after Watson and Crick discovered the structure of DNA, however, scientists debated exactly how the bases were oriented to each other when the hydrogen bonds were made.

Watson and Crick proposed one orientation and several years later a biochemist named Karst Hoogsteen found that the bonds could still form if the As and Gs were flipped upside down. 

Al Hashimi has been studying these two orientations for years. Several years ago, he discovered that DNA can spontaneously switch back and forth between the two states. The bases only took on the upside-down Hoogsteen orientation about one percent of the time, but Hoogsteen's always tended to show up in places where the DNA attached to a protein or where the DNA was damaged by wayward chemicals.

In this study, Al Hashimi and his colleagues used a specific type of chemical imaging technology called NMR relaxation dispersion, which is based on the same technology as an MRI machine, to see if and how RNA molecules in a double helix make Hoogsteen-style bonds.

Hoogsteen/Watson and CrickThe short answer is, they don’t. While DNA makes Hoogsteens about one percent of the time, no matter what sequence of A, U, C and G Al Hashimi tried, RNA would never make a Hoogsteen-style bond. Even when the researchers chemically attacked RNA with a molecule that forces DNA into a Hoogsteen formation, RNA could not make that bond work. Instead, the RNA strand just split apart.

While that may not seem like a huge deficiency, the fact that DNA uses Hoogsteen areas to latch onto functional proteins to get work done around a cell and resist chemical attacks makes the fact that RNA simply can’t do the same thing a glaring deficiency.

Bringing this back to Toy Story, imagine you have cloth-doll, cowboy Woody (RNA) and plastic, spaceman action-figure Buzz (DNA). Not only does Buzz stand taller and hold his shape better, but his tough, plastic frame contains notches to attach cool accessories like jet packs and his kung-fu grip can hold a ray gun. Woody would just flump down if by some miracle you could even get those things to stay on him. Further, if you were to spill some damaging chemical like apple juice onto Buzz, the worst thing that would happen is he’d get a little sticky until you could run him under some water. Woody, on the other hand, would just absorb the liquid right into his cloth and stuffing, and every time you wash him, he would start to fray just a little bit more.

Al Hashimi suspects that the reason RNA can’t form the Moogsteen bonds is because its double helix coil is too tight, and the bases can’t flip without crashing into each other. Whatever the reason, this research provides another fundamental reason why RNA took a back seat on the toy shelf of molecular evolution.

—Daniel Lane

Daniel Lane covers science, medicine, engineering and the environment in North Carolina.