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Why is uracil, rather than thymine, used in RNA?

Why is uracil, rather than thymine, used in RNA?



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This question was posed on SE Biology some time ago, but all the answers, including the accepted one, answered a different question instead: “Why is thymine, rather than uracil, used in DNA?”. I therefore changed the title to match the answers, giving notice that, if the change were approved, I'd post the original separately question myself (and answer it, if necessary). Here it is:

It is believed that thymine replaced uracil (the RNA base) in DNA because of the deleterious effects of slow spontaneous deamination of cytosine to uracil: by employing thymine instead of uracil, any uracil in DNA would clearly be aberrant, allowing a specific mechanism of repair (involving uracil DNA glycosylase) to evolve with impunity. As this was clearly advantageous, why didn't RNA also evolve to use thymine instead of uracil?

N.B. By “why?” I mean “how can one rationalize the fact that?”. Obviously, the answer to this type of question is not, and probably cannot be, known with certainty.


Regardless of the question† of which came first*, RNA or DNA, it is possible to rationalize the absence of thymine in RNA by a cost-benefit analysis. There is a cost to using thymine, so there must be sufficient benefits to make this worth while.

Cost of using thymine rather than uracil

The most obvious cost of using thymine is the energy requirement for its synthesis (in terms of reducing power - NADPH).

An analogous conversion of rUMP to rTMP (if it existed) would incur similar costs. (There may be additional costs, but they may be contentious and this is indisputable, so it will suffice.)

Benefit of using thymine rather than uracil

For DNA the benefit is clear and stated in the question. By not using uracil as the complement to adenine, uracil produced by spontaneous deamination of cytosine can be recognized as abberant and removed by the DNA proof-reading repair systems. This presumably gives the organism an advantage (benefit) by reducing harmful mutations to DNA - the genetic material.

RNA is not the genetic material of contemporary autonomous organisms. Hence unrepaired C to U deaminations will not affect that aspect of the viability of an organism. How serious will they be for the cell, though? The largest and most long-lived RNAs are the structural ribosomal RNAs. Such mutations in the cells rRNA might have no effect on ribosome function as much of the RNA is thought to be structural. However, even if they did, the inactivation of a small percentage of the ribosomes of a cell would have little impact on protein synthesis. Likewise for the small tRNA molecules.

Messenger RNA poses a different problem as we can conclude that abberant proteins made from mutant mRNA are dangerous to the cell from the fact that a proof-reading mechanism exists to correct errors in the charging (aminoacylation) of tRNAs. I would argue that the relatively short half-life of mRNA compared with the frequency of deamination of cytosine means that the latter process is not responsible for a significant amount of mutant mRNA.

Conclusion

The benefits of using thymine - together with a repair system - in RNA would be marginal, and hence not worth the energetic cost this would entail.

†Footnote: We don't need to argue about which nucleic acid came first

The current metabolic pathways for formation of dTTP from dUTP and the reduction of ribose to deoxyribose are strongly suggestive to me that RNA preceeded DNA in evolution. (They suggest nothing about whether RNA preceeded protein.) However, the rationalization presented here does not require this assumption. If DNA came first and RNA initially had T instead of U, the rationale could be used to argue why RNA changed bases from T to U. Indeed, the rationale can be employed by those who do not even believe in evolution - they could argue (and probably do) that some deity created things that way because it was more efficient in terms of cost-benefit.


Answering this question accurately is difficult as it touches on the origin of life hypothesis. In the RNA World Hypothesis, RNA is the original "life" that is able to catalyze its own self-replication. There are various evidences of support for this hypothesis. Uracil's structure is relatively easy to synthesize in reactions that plausibly could take place on early Earth conditions. It could be that RNA used Uracil simply because of Uracil's abundance in nature. This seems to be the case for the use of Adenine in ATP. Guanine can also be used in an energy carrying molecule GTP, but those instances are vastly outnumbered by ATP.

However, there's no set in stone theory as to why either RNA uses Uracil instead of Thymine, or DNA uses Thymine instead of Uracil. Only a lot of circumstantial evidence. The inverse argument for DNA's use of Thymine could also support RNA's use of Uracil. In a competitive environment, a higher mutation rate afforded by the deamination of Cytosine to Uracil may have been an advantage to quickly promote change.


Why is there thymine in DNA and uracil in RNA?

Additionally, why does adenine pair with uracil in RNA? In RNA, uracil base-pairs with adenine and replaces thymine during DNA transcription. In DNA, the evolutionary substitution of thymine for uracil may have increased DNA stability and improved the efficiency of DNA replication (discussed below). Uracil pairs with adenine through hydrogen bonding.

Accordingly, what happens if uracil is in DNA?

Uracil in DNA results from deamination of cytosine, resulting in mutagenic U : G mispairs, and misincorporation of dUMP, which gives a less harmful U : A pair. At least four different human DNA glycosylases may remove uracil and thus generate an abasic site, which is itself cytotoxic and potentially mutagenic.

What is the difference between thymine and uracil?

The only difference between thymine and uracil is a methyl group - thymine has it, uracil doesn't. Cytosine pairs with guanine, whereas adenine pairs with uracil in the transcription process.


What is DNA?

To begin with, we must start with probably the best known of the three macromolecules (“big molecules”) we will be looking at today: DNA.

DNA stands for “deoxyribonucleic acid.” DNA is a large, complex molecule that carries and passes down the genetic code that makes up all living organisms. Because most people are at least somewhat aware of DNA’s very important role in life, DNA has come to metaphorically refer to “the set of nongenetic traits, qualities, or features that characterize a person or thing.” For example, we would say a love of words is part of the DNA of Dictionary.com.

DNA is found in the nucleus of cells of all living organisms. DNA is arranged in the shape of a double helix, which resembles a twisted ladder. The “rungs” of the ladder consist of base pairs of substances known as nitrogen bases. You might remember the four bases from science class: adenine, thymine, guanine, and cytosine. These base pairs are the reason why DNA is so important to life: the ordering of the base pairs results in a specific genetic code called a gene.

DNA consists of many genes and is itself organized into structures known as chromosomes, of which humans have 23 pairs. A fruit fly has four pairs of chromosomes, while a dog has 39 pairs. The genetic code in the genes and DNA tell the body how to make proteins. Proteins are extremely important for the survival of the body and you would be in big trouble if your cells couldn’t make proteins or accidentally made the wrong proteins.

We have merely scratched the surface of the complicated molecule that is DNA. To get a better idea of how important DNA is, here are some vocabulary words that explore concepts that are related to DNA:


Researchers unlock secret of RNA's versatility

Evidence is in that could help explain the variety of complex shapes that RNA--ribonucleic acid--assumes to carry out its many biological functions.

RNA is the workhorse of the genetic world, transcribing the coded instructions of DNA and assembling amino acids into proteins. It has been shown that chains of RNA can fold back on themselves and assume complex formations that enable them to perform their tasks. Until now, however, there has been little or no detailed information to explain RNA's amazing versatility.

Stephen Holbrook, a chemist in the Structural Biology Division, has found that uracil, one of the four types of nitrogenous "bases" that represent the letters of the genetic code, can pair off with any other letter, including itself. This contradicts the exclusive two-letter base-pairing pattern in DNA, which was first discovered by Nobel laureates Francis Crick and James Watson.

"Uracil can now be called the universal partner in RNA structure," says Holbrook. "That it can pair with any other base helps explain why RNA is so flexible in terms of how it interacts with itself and why, unlike DNA, it can take on so many different shapes." DNA has only one form--the double helix.

Determining the structure of biological macromolecules such as RNA requires that the material first be crystallized so that its atoms are firmly fixed in an orderly pattern. This pattern can then be identified by sending a beam of x-rays through the crystal (the x-rays are diffracted or scattered by the atoms). Whereas other researchers have used x-ray crystallography to determine protein structural shapes, Holbrook is one of the few to use it to study the structural shapes of RNA. He attributes this in part to the difficulty in synthesizing, purifying, and, ultimately, crystallizing RNA.

"Virtually all crystallizations of DNA have resulted from similar conditions of salt, buffer, precipitant, and additives, but these standard conditions are not successful for many of the different forms of RNA," says Holbrook. He and his research group have been experimenting with novel ways of crystallizing RNA, focusing on sequences of base-pairs that form structures known as "internal loops."

One of the first results of Holbrook's crystallization research was the direct observation of an RNA double helix formation that incorporated four unconventional base-pairs. Watson and Crick demonstrated that DNA's double helix is held together by chemical bonds formed between complementary pairs of bases. These complementary base-pairs are cytosine (C) and guanine (G), and adenine (A) and thymine (T). RNA has a similar structure, except that thymine is represented by uracil (U).

Watson-Crick base-pairs--C-G and A-T (or A-U in RNA)--were once thought to be the only arrangement possible in nature. Holbrook's crystals however, showed two uracil-guanine (U-G) and two uracil-cytosine (U-C) base pairs in the middle of the sequence. This mismatched pairing resulted in the formation of a stable RNA double helix in the crystal with just a slight shape distortion.

"The U-C base pairs were joined by only a single hydrogen bond (conventional base-pairs are joined by two or three bonds)," says Holbrook, "but were stabilized by the presence of numerous, tightly bound water molecules."

Holbrook subsequently determined the three-dimensional structure of an RNA molecule containing U-U base pairs. Unlike the U-G and U-C base pairs, the U-U partners formed two hydrogen bonds that were stable without the presence of tightly bound water molecules.

"Non-standard base pairs such as the U-G, U-C, and U-U partners we have observed are common in ribosomal RNA, viroids, messenger RNA, and retroviruses," says Holbrook. "Runs of these mismatched pairs in the middle of double helical RNA form internal loops."

To date, Holbrook's best x-ray crystallography images have come when using the facilities at the Stanford Synchrotron Radiation Laboratory. Although SSRL's resolution of about two angstroms provided him with "the clearest views ever obtained of RNA structures," it was still not as high as he would have liked. When the x-ray crystallography beamline opens at the Advanced Light Source, he will probably be one of its first users.

"The availability, proximity, and unique facilities for measurement of x-ray diffraction data at the ALS crystallography beam will allow us to collect data much faster and determine molecular structures which would not otherwise be feasible," Holbrook says.

With the improved resolution and other advantages of the ALS, Holbrook says he would like to tackle longer and more complex stretches of RNA. "If we know the shape of an RNA structure and can design molecules that will bind to it," he says, "we can then study and possibly control the function of that structure."

KEY TERMS

Base pairs--Two nucleotides (i.e., cytosine and guanine, or adenine and thymine) that are joined by weak bonds. The bonds between base pairs hold together DNA's two strands into the shape of the double-helix.

DNA--Deoxyribonucleic acid, the double-stranded molecule in the shape of a double-helix that encodes the genetic information which determines the sequence of amino acids in protein synthesis.

Protein--A large molecule composed of chains of amino acids arranged in a specific sequence according to the instructions in the genetic code. Proteins are responsible for the structure, function, and regulation of living cells.

RNA--Ribonucleic acid, a molecule similar in structure to DNA that is found in the nucleus and cytoplasm of cells and plays an important role in protein synthesis and other vital chemical activities.

X-ray crystallography--A technique for determining the location of atoms in a crystal, based on the diffraction pattern created when a beam of x-rays is passed through the crystal.


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What’s RNA and its structure

RNA is one of the very important organic molecules in genetic, next after DNA.

RNA (Ribonucleic acid) is a nucleic acid present in all living cells and its principal role is to act as a messenger carrying instructions from DNA for controlling the synthesis of proteins.

It is important to note that in living organisms, DNA is the prime storehouse of genetic information, and RNA is formed from that DNA whenever the need for the formation of proteins arises.

Although in some viruses (like retrovirus), RNA rather than DNA carries genetic information.

In these non-living viruses, RNA is present which replicates, stores genetic information, and only gets expressed as (DNA → mRNA → Protein) if the virus enters a living host cell.

  1. Ribose Pentose Sugar
  2. Phosphate Group
  3. One of any four Nitrogenous bases: Adenine(A), Guanine(G), Cytosine(C), and Uracil(U)

RNA has Uracil instead of Thymine. The other three N-bases viz. Adenine, Guanine, and Cytosine are the same as in the case of DNA.

Uracil (U) base is also a pyrimidine and is very similar to that of DNA’s thymine (T).

Now, let’s know about the importance of RNA. There are 9 important reasons to consider. Let’s know about these.


Thymine-less cell death

Figure 7: If dUTP:dTTP
increases, DNA polymerase
frequently incorporates uracil
instead of thymine during
both replication and repair.
Uracil-DNA glycosylase
removes the uracil and
initiates further repair
involving DNA strand breaks
in an intermediate step.
Repair synthesis, however,
may reintroduce uracil,
leading to a futile DNA repair
cycle. Eventually, the system
is overloaded and
chromosome fragmentation
occurs, leading to cell death.
Click to enlarge image

Image courtesy of Angéla
Békési

When DNA is synthesised, the DNA polymerase enzymes (which catalyse the synthesis) cannot discriminate between thymine and uracil. They only check whether the hydrogen bonds form correctly, i.e. whether the base pairs are matched properly. To these enzymes, it does not matter whether thymine or uracil binds to adenine. Normally, the amounts of deoxyuridine triphosphate (dUTP, a source of uracil) in the cell are kept very low compared to levels of deoxythymidine triphosphate (dTTP, a thymine source), preventing uracil incorporation during DNA synthesis.

If this strict regulation is perturbed and the ratio of dUTP to dTTP rises, the amount of uracil that is incorrectly incorporated into DNA also increases. The repair system – which, unlike DNA polymerases, can distinguish uracil from thymine – then attempts to cut out the uracil with the help of uracil-DNA glycosylase and to re-synthesise the DNA, which involves temporarily cleaving (cutting) the DNA backbone. However, if the ratio of dUTP to dTTP is still elevated, this re-synthesis may again incorporate uracil instead of thymine. This cycle eventually leads to DNA strand breaks and chromosome fragmentation, when these temporary cuts in the DNA happen one after the other and too close to each other (see Figure 7). This results in a specific type of programmed cell death, called thymine-less cell death.

The process of thymine-less cell death can be deliberately exploited in the treatment of cancer. Because cancer cells proliferate at such a high rate compared to normal cells, they synthesise a greater amount of DNA per given time period and therefore require large amounts of dUTP. By raising the ratio of dUTP to dTTP, these cancer cells can be selectively targeted and eliminated.


What is Uracil

Uracil is one of the pyrimidine bases found only in RNA. It contains two keto groups at C-2 and C-4 of its heterocyclic pyrimidine ring. Uracil attaches to ribose through a glycosidic bond, forming the nucleoside, uridine. The phosphorylation of uridine produces its mono-, di- and triphosphates. In RNA, uracil complementary base pairs with adenine via two hydrogen bonds. Uracil is capable of base pairing with other bases in the RNA strand depending on the arrangement. It rarely occurs in DNA as an evolutionary change, which increases the DNA stability. Uridine nucleotides serve as allosteric regulators and coenzymes in plants and humans. Uracil is a weak acid. Therefore, it undergoes oxidation, alkylation, and nitration. It also reacts with elemental halogens. Uracil is capable of absorbing UV.

Figure 1: Uracil


The Central Dogma of Biology

There are several different kinds of RNA made by the cell. mRNA - messenger RNA is a copy of a gene. It acts as a photocpoy of a gene by having a sequence complementary to one strand of the DNA and identical to the other strand. The mRNA acts as a busboy to carry the information stored in the DNA in the nucleus to the cytoplasm where the ribosomes can make it into protein.

tRNA - transfer RNA is a small RNA that has a very specific secondary and tertiary structure such that it can bind an amino acid at one end, and mRNA at the other end. It acts as an adaptor to carry the amino acid elements of a protein to the appropriate place as coded for by the mRNA.

rRNA - ribosomal RNA is one of the structural components of the ribosome. It has sequence complementarity to regions of the mRNA so that the ribosome knows where to bind to an mRNA it needs to make protein from.

snRNA - small nuclear RNA is involved in the machinery that processes RNA's as they travel between the nucleus and the cytoplasm. We will discuss these later in the context of eukaryotic gene structure.

The Genetic Code

Note the degeneracy of the genetic code. Each amino acid might have up to six codons that specify it. It is also interesting to note that different organisms have different frequencies of codon usage. A giraffe might use CGC for arginine much more often than CGA, and the reverse might be true for a sperm whale. Another interesting point is that some species vary from the codon association described above, and use different codons fo different amino acids. In general, however, the code depicted can be relied upon.

How do tRNAs recognize to which codon to bring an amino acid? The tRNA has an anticodon on its mRNA-binding end that is complementary to the codon on the mRNA. Each tRNA only binds the appropriate amino acid for its anticodon.


Why is uracil, rather than thymine, used in RNA? - Biology

Great question! However, the real question is: Why does thymine replace uracil in DNA?

First, some clarification. As you already know, the difference between RNA (ribonucleic acids) and DNA (deoxyribonucleic acids) is the existence of a hydroxyl (-OH) group on the 2' carbon of the ribose sugar in the backbone. The removal of 2' hydroxyl groups from DNA does not occur after the DNA has been synthesized, but rather the 2' hydroxyl groups are removed from the nucleotides before they are incorporated into the DNA. During nucleotide synthesis, a portion of the nucleotide monophosphates (NMP's) are dehydroxylated to 2'-deoxy-nucleotide monophosphates (dNMP's). This means that GMP, AMP, CMP, and UMP are converted into dGMP, dAMP, dCMP, and dUMP, respectively. However, before being incorporated into the chromosomes, another modification, using folic acid as a catalyst, methylates the uracil in dUMP to form a thymine making it dTMP. After further phosphorylation, dGTP, dATP, dCTP, and dTTP can be used as the building blocks to construct DNA.

The important thing to notice is that while uracil exists as both uridine (U) and deoxy-uridine (dU), thymine only exists as deoxy-thymidine (dT). So the question becomes: Why do cells go to the trouble of methylating uracil to thymine before it can be used in DNA?

The answer is: methylation protects the DNA. Beside using dT instead of dU, most organisms also use various enzymes to modify DNA after it has been synthesized. Two such enzymes, dam and dcm methylate adenines and cytosines, respectively, along the entire DNA strand. This methylation makes the DNA unrecognizable to many Nucleases (enzymes which break down DNA and RNA), so that it cannot be easily attacked by invaders, like viruses or certain bacteria. Obviously, methylating the nucleotides before they are incorporated ensures that the entire strand of DNA is protected. Thymine also protects the DNA in another way. If you look at the components of nucleic acids, phosphates, sugars, and bases, you see that they are all very hydrophilic (water soluble). Obviously, adding a hydrophobic (water insoluble) methyl group to part of the DNA is going to change the characteristics of the molecule. The major effect is that the methyl group will be repelled by the rest of the DNA, moving it to a fixed position in the major groove of the helix. This solves an important problem with uracil - though it prefers adenine, uracil can base-pair with almost any other base, including itself, depending on how it situates itself in the helix. By tacking it down to a single conformation, the methyl group restricts uracil (thymine) to pairing only with adenine. This greatly improves the efficiency of DNA replication, by reducing the rate of mismatches, and thus mutations.

To sum up: the replacement of thymine for uracil in DNA protects the DNA from attack and maintains the fidelity of DNA replication. (For another take on DNA, check out this article:
Inhibition of Ribozymes by Deoxyribonucleotides and the Origin of DNA.)

[Moderator Note: In addtion, the cytosine base can spontaneously deaminate to form a uracil base, which would result in undetectable C -> U mutations if U were used routinely in DNA. Since Thymine is basically methyl-U, the cell's DNA repair mechanisms can distinguish illegitimate U from legitimate methyl-U in DNA, and make the proper repair (replacing any U with a C). C -> U mutations in RNA do not matter as much, because RNA is synthesized in large quantities and is rapidly degraded in comparison to DNA. -- Steve Mack, MadSci Moderator.]

Try the links in the MadSci Library for more information on Biochemistry.


Thymine vs. Uracil

We all know from high school bio that thymine takes the place of uracil in DNA. But why exactly does this occur? What advantage does thymine offer over uracil?

When I asked a teacher about this, she replied: Thymine is a more stable molecule than uracil, and thus helps maintain the integrity of DNA.

However, the only difference between these two bases is a single methyl group:

So how exactly does that small change stabilize DNA?

For one, it prevents DNA from being recognized and chopped up by nucleases - the methyl group thus helps to protect DNA against invaders. The hydrophobic effect of the methyl group also helps to ensure proper base pairing (uracil can occasionally pair with other bases). Thymine&rsquos methyl group also provides a point of interaction for amino acids in proteins (possibly resulting in better recognition by polymerases, transcription factors, etc).

Perhaps the strongest impetus, though, for the incorporation of thymine into DNA comes from the spontaneous deamination of cytosine. This undesirable chemical reaction results in a uracil base, and occurs, on average, 100 times per day in a mammalian cell.

The buildup of these &ldquoillegitimate&rdquo uracils could be catastrophic for the organism - at the very least, copying fidelity of DNA would be detrimentally affected. Thus, cells have repair systems in place to remove these &ldquoillegitimate&rdquo uracils. But if uracil were already present in DNA, paired to adenine, the repair system would be forced to somehow differentiate between &ldquoillegitimate&rdquo and &ldquolegitimate&rdquo uracils. An easy solution to this problem? Add a methyl group to all of the &ldquolegitimate&rdquo uracils, allowing the repair system to easily tell between the two. This usage of methylated uracil, or thymine, in DNA allowed for the long-term storage of crucial genetic information.