Question

Why did mother nature use uracil to replace thymine in mRNA (messenger ribonucleic acid)? What is the advantage of using U instead of T in the RNA?

Al Frisby, Biology Teacher, Liberty High School, Liberty, MO

From the Editors:
This is a good question, an interesting extension of Paleogenetics, the study of ancient DNA. Here we wonder not just what the genetic encoding looked like, but how it came to be. A better question may be: Why does thymine replace uracil in DNA? Since it takes energy to convert uracil to thymine (by adding a methyl group), why do cells expend the energy required to methylate uracil to thymine for use in DNA?

One reason is to protect the DNA. Methylation of bases protects the DNA by making it unrecognizable to many nucleases—enzymes that can break down DNA—and thus defending it from attack by invaders like bacteria and viruses. Since RNA is shorter-lived than DNA, it can get by with the energetically “cheaper” uracil. Also, adding the hydrophobic methyl group changes the shape of the DNA molecule and allows thymine to base-pair only with adenine, whereas uracil would base-pair less selectively. Finally, using thymine allows more effective recognition and repair of potentially harmful cytosine to uracil mutations, as explained by Dr. Greg Freyer.

Answer

In DNA, cytosine is readily deaminated, forming uracil. This occurs at a rate of 1,000 to 10,000 times per cell per day. This altered base is recognized very efficiently by uracil DNA glycosylase (UDG), which cleaves it creating an abasic site.  This site is then removed and replaced by cytosine, restoring the DNA back to its original—and correct—sequence.  This process of repair is referred to as base excision repair (BER) and is probably the major system responsible for maintaining the integrity of the cell’s DNA.  For example, BER is responsible for repairing abasic sites, some types of DNA damage caused by UV light (a physical carcinogen), and many other types of DNA damage (e.g., chemical carcinogens such as benzene; or biological carcinogens such as the HIV virus).

If uracil were present in DNA, then the cell would have a difficult time deciding whether the uracil generated from a mutation—the deamination of cytosine—should be there or not.  If uracil were used instead of thymine, then the cell would have no logical way of readily distinguishing legitimate uracil from uracil produced by the mutation of cytosine, and thus knowing which uracil base to repair and which to leave alone.  By using thymine in DNA this issue is avoided. Again, RNA uses the “cheaper” uracil since these C to U mutations are not as harmful in RNA, because it is shorter-lived and synthesized in greater quantities compared to DNA. This explanation, while not a fact or certaintly, is sensible and well regarded.

This answer is from Greg A. Freyer, Ph.D., Associate Professor, Department of Anatomy and Cell Biology Columbia University, New York, NY

Another Expert Responds:
While it may not be known as scientific fact that this was a substitution per se, as opposed to a divergence, the difference, as with so many manifestations of evolution, likely arose from a random genetic mutation in mRNA that led to a molecular structure with equal or greater advantageousness. The uracil probably exists for a couple reasons at the molecular level as a result of enzymatic recognition. The first is that uracil was recognized better by the primordial RNA polymerase enzyme-like protein, and that stuck through the emergence of cells and evolution to current RNA polymerases.

A second possibility is that RNA polymerase evolved to prefer uracil so as not to compete with DNA polymerases for thymine in primitive cells, should there be an evolutionary advantage to this in transcription (RNA synthesis) or translation (protein synthesis). From a chemical standpoint, examination might show that enzymatic efficiency of transcription is higher with uracil than it would be with thymine, and that enzymes that used uracil survived. This is not true for DNA, which is pretty stable and capable of employing thymine.

This answer is from Michael Sturr, Ph.D., Microbiologist and Science Educator, Mountainside, NJ