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| Lead Editor: Bob MossNUCLEIC ACID STRUCTURE AND FUNCTION

By: Suzanne Clancy, Ph.D. 2008 Nature Education

Chemical Structure of RNA

Figure 1

Figure 3

Figure 2

Figure 4

Aa Aa Aa

The more researchers examine RNA, the more surprises they continue to uncover. What have we learned about RNA

structure and function so far?

With the discovery of the molecular structure of the DNA double helix in 1953, researchers turned to the structure of

ribonucleic acid(RNA) as the next critical puzzle to be solved on the road to understanding the molecular basis of life.

Indeed, RNA may be the only molecule to have inspired the formation of a club, known as the RNATie Club, whose

members included Nobel Laureates James Watson and Francis Crick, the discoverers of DNA structure, as well as Sydney

Brenner, who was awarded the Nobel Prize in 2002 for his work involv ing generegulation in the model organism

Caenorhabditis elegans. The members of this club, each nicknamed for aparticular amino acid, exchanged letters in which

they presented various unpublished ideas in an attempt to understand the structure of RNAand how this moleculeparticipates in the building of proteins. During the following 50 years, many questions were answered, and many surprises

were uncovered along the way.

Early Discoveries of RNA StructureToday, researchers know that cells contain a variety of forms of RNA-incl uding messenger RNA(mRNA), transfer RNA

(tRNA), and ribosomal RNA (rRNA)-and each form is involved in different functions and activities. Messenger RNAis

essentially a copy of a section of DNA and serves as a template for the manufacture of one or more proteins. Transfer RNA

binds to both mRNA and amino acids (the building blocks of proteins) and brings the correct amino acids into the growing

polypeptidechain during protein formation, based on the nucleotide sequence of the mRNA. The process by which proteins

are built is called translation.Translation occurs on ribosomes,which are cellular organelles composed of proteinand rRNA.

Although there are multiple types of RNA molecules, the basic structure of all RNA is similar. Each kind of RNA is a

polymeric molecule made by stringing together individual ribonucleotides, always by adding the 5'-phosphate group of one

nucleotide onto the 3'-hydroxyl group of the previous nucleotide. Like DNA, each RNA strand has the same basic structure,

composed of nitrogenous bases covalently bound to a sugar-phosphate backbone(Figure 1). However, unlike DNA, RNAis

usually a single-stranded molecule. Also, the sugar in RNA is ribose instead of deoxyribose (ribose contains one more

hydroxyl group on the second carbon), which accounts for the molecule's name. RNA consists of four nitrogenous bases:

adenine, cytosine, uracil, and guanine. Uracil is a pyrimidine that is structurally similar to the thymine, another pyrimidine that

is found in DNA. Like thymine, uracilcan base-pair with adenine(Figure 2).

Although RNA is a single-stranded molecule, researchers soon discovered that it can form double-stranded structures,

which are important to its function. In 1956, Alexander Rich-an X-ray crystallographer and member of the RNATie Club-and

David Davies, both working at the National Institutes of Health, discovered that single strands of RNA can "hybridize,"

sticking together to form a double-stranded molecule(Rich & Davies, 1956). Later, in 1960, the discovery that an RNA

molecule and a DNAmolecule could form a hybrid double helix was the first experimental demonstration of a way in which

information could be transferred from DNAto RNA(Rich, 1960).

Single-stranded RNA can also form many secondary structures in which a single RNAmolecule folds over and forms hairpinloops, stabilized by intramolecular hydrogen bonds between complementary bases. Such base-pairing of RNA is critical for

many RNA functions, such as the ability of tRNA to bind to the correct sequence of mRNAduring translation(Figure 3).

Indeed, Robert Holley, a chemist at Cornell University, was the first researcher to work out the structure of tRNA(Holley et al., 1965). This molecule

turned out to be the elusive structure that Francis Crick proposed in his so-called "adapter hypothesis" of 1955-a structure that carried amino acids

and arranged them in a certain order that corresponded to the sequence in the nucleic acidstrand. In 1968, Holley was awarded the Nobel Prize in

Physiology or Medicine together with Gobind Khorana, at the University of Wisconsin, and Marshall Nirenberg, at the National Institutes of Health.

Nirenberg and Khorana devised the key experiments to decipher the genetic code-in other words, which sequences of three nucleotides (codons) in

an mRNAmolecule would code for which amino acids.

mRNA and SplicingSeveral forms of RNA play pivotal roles in gene expression-the process responsible for manifesting the instructions stored in

the sequence of DNA nucleotides in either RNAor protein molecules that carry out the cell's activities (Figures 4 and 5).

Messenger RNA (mRNA) is particularly important in this process. mRNA is primarily composed of coding sequences that is,it carries the genetic information for the amino acid sequence of a proteinto the ribosome, where that particular protein is

synthesized. In addition, each mRNAmolecule also contains noncoding, or untranslated, sequences that may carry

instructions for how the mRNA is handled by the cell(Figure 6). For example, the untranslated regionat the 5' end of the mRNA molecules found in

Citation: Clancy, S. (2008) Chemical structure of RNA. Nature Education1(1):223
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Figure 5

Figure 6

Figure 8

Figure 9

bacteria and other prokaryotes contains what is called a Shine-Dalgarno sequence, which aids in the binding of the mRNAto ribosomes.

In contrast, the mRNAof eukaryoticorganisms is prepared for translation through more complex mechanisms. For one, the

addition of a guaninenucleotidewith a methyl (CH3) group to the 5' end of the mRNA, called the 5' cap, increases the

stability of the mRNA and assists in the binding of the mRNAto the ribosomefor translation. Meanwhile, another

untranslated region is added to the 3' endof the mRNA, thereby further affecting the stability of the molecule. In this case, a

"tail" consisting of anywhere from 50 to 250 adenine nucleotides is added to the 3' end. This poly(A) tail can increase the

stability of many mRNA molecules, depending on the proteins that attach to it. The greater the stability, and the longer an

mRNAmoleculeexists in a cell, the more protein that can be made from that molecule.

In eukaryotes (and to a lesser extent, prokaryotes), when RNA is first transcribed from DNA, it may contain additional noncoding sequences that are

interspersed within the coding sequence. This immature RNAmolecule is referred to as precursor mRNA(pre-mRNA) or heterogeneous nuclearRNA(hnRNA). The intervening noncoding sequences are called introns, and the segments of coding are known as material exons. The introns are

then removed by a process known as RNAsplicingto produce the mature mRNAmolecule(Figure 7). An organelle called the spliceosome,

composed of proteinand small nuclear RNAs (snRNAs), is responsible for recognizing and removing the introns from pre-mRNA.

The surprising discovery of RNAsplicing caused a paradigm shift in genetics. Much early work indicated that mRNAand the

genes in DNAwere colinear that is, they were thought to match up, basefor base, with the exception of the 3' poly(A) tail.

In the late 1970s, however, seminal studies of gene expression in cells infected with an adenovirus demonstrated that the

RNA transcripts produced by viral infection contained sequences that were not next to one another in the viral genome.

Further study revealed that these mRNAs were produced after material had been removed or spliced out of a larger primary

transcript (Berget et al., 1977 Evans et al., 1977). Since that time, introns have been found to occur in many eukaryotic cellular genes and some

prokaryotic genes.

Probably the most thoroughly studied class of introns consists of those found in protein-coding genes. The 5' end of these introns almost always

begins with the dinucleotide GU, and the 3' end typically contains AG. Changing one of these nucleotides precludes splicing. Another importantsequence occurs at the branch point, anywhere from 18 to 40 nucleotides upstream from the 3' end of an intron. This sequence always contains an

adenine, but it is otherwise loosely conserved. A typical sequence at a branchpoint is YNYYRAY, where Y indicates a pyrimidine, N denotes any

nucleotide, R any purine, and A is for adenine(Figure 8) (Pierce, 2000 Patel & Steitz, 2003).

Many eukaryotic genes can be spliced in a number of different ways by choosing between different potential 5 and 3 splice junctions, thereby

creating different combinations of exons and introns in the final mRNAs. This mix-and-match process allows the creation of several different proteins

from a single gene sequence. The first example of such "alternative splicing" (Figure 9) was discovered in the adenovirus in 1977 (Berget et al.,

1977). The first example in cellular genes was reported in 1980 in the IgMgene, which encodes an immunoglobulin, one of several proteins created

by immune cells to fight infection by foreign organisms and particles (Early et al., 1980).

The Dscamgeneof Drosophila, which encodes proteins involved in guiding embryonic nerves to their target destinations during formation of the fly's

nervous system, exhibits an especially impressive number of alternative splicing patterns. Dozens of different forms of Dscam mRNAs and

corresponding proteins have been identified, while analysis of the gene's sequence reveals a staggering 38,000 potential additional mRNAs, based

on the large number of introns found. The ability to produce so many different proteins from a single gene may be necessary for forming as complex

a structure as the nervous system (Schmucker et al., 2000). In general, the existence of multiple mRNA transcripts from single genes may account

for the complexity of some organisms, such as humans, even though these organisms have relatively few genes (in the case of humans,

approximately 25,000).

Figure 7: Gene organization and the intron.

Used with permission. 2005 by W. H. Freeman and Company. All rights reserved.

tRNA and rRNA: Their Role in TranslationTwo additional categories of RNA play a critical role in the translation process: tRNAand rRNA. R ibosomal RNA(rRNA)

molecules were initially characterized by how rapidly they would "sink" in a centrifuge tube-in other words, they were

described by their sedimentation velocity as measured in Svedberg (S) units. Prokaryotic organisms contain one type of

rRNAgene that encodes three distinct RNAspecies: the 23S, 5S, and 16S rRNAs. In comparison, eukaryotic cells contain

two types of rRNA genes that give rise to four rRNAspecies: the 28S, 5.8S, 5S, and 18S rRNAs. Both the eukaryotic and prokaryotic genomes

contain multiple copies of these rRNA genes to be able to manufacture the large number of ribosomes required by a cell. Mature rRNAs are

produced by cleavage and modification of initial transcripts (Pierce, 2000).

Transfer RNA(tRNA) molecules serve as molecular adaptors that bind to mRNA on one end and carry amino acids into

position on the other. Most types of cells possess approximately 30 to 40 different tRNAs, with more than one tRNA

corresponding to each amino acid. tRNAs fold into a cloverleaf structure held together by the pairing of complementary

nucleotides. Structural studies using X-ray crystallography have demonstrated that the cloverleaf is further folded into an L

shape (Figure 10). A loop at one end of the folded structure base-pairs with three nucleotides on the mRNAthat are

collectively called a codon the complementary three nucleotides on the tRNA are called the anticodon.
http://www.whfreeman.com/http://www.nature.com/scitable/topicpage/RNA-Splicing-Introns-Exons-and-Spliceosome-12375http://www.nature.com/scitable/topicpage/RNA-Splicing-Introns-Exons-and-Spliceosome-12375http://disporigimg%28%22ne0000/ne0000/ne0000/ne0000/95777/DNA_alternative_splicing_FULL.jpg%22,%20%22A%20schematic%20representation%20of%20alternative%20splicing.%22,%20%22Y%22,%20%22Figure%209%22,%20%221224097847289-2718398148_9%22,%20'Y',%20%22%22,%20'900',%20'441',%20%22%22);http://disporigimg%28%22ne0000/ne0000/ne0000/ne0000/95777/DNA_alternative_splicing_FULL.jpg%22,%20%22A%20schematic%20representation%20of%20alternative%20splicing.%22,%20%22Y%22,%20%22Figure%209%22,%20%221224097847289-2718398148_9%22,%20'Y',%20%22%22,%20'900',%20'441',%20%22%22);http://disporigimg%28%22ne0000/ne0000/ne0000/ne0000/95777/DNA_alternative_splicing_FULL.jpg%22,%20%22A%20schematic%20representation%20of%20alternative%20splicing.%22,%20%22Y%22,%20%22Figure%209%22,%20%221224097847289-2718398148_9%22,%20'Y',%20%22%22,%20'900',%20'441',%20%22%22);http://disporigimg%28%223711/pierce_14_10_FULL.jpg%22,%20%22Splicing%20of%20pre-mRNA%20requires%20consensus%20sequences.%22,%20%22Y%22,%20%22Figure%208%22,%20%221224097819597-5346069765_8%22,%20'Y',%20%22Used%20with%20permission.%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'430',%20'123',%20%22http://www.whfreeman.com%22);http://disporigimg%28%223711/pierce_14_10_FULL.jpg%22,%20%22Splicing%20of%20pre-mRNA%20requires%20consensus%20sequences.%22,%20%22Y%22,%20%22Figure%208%22,%20%221224097819597-5346069765_8%22,%20'Y',%20%22Used%20with%20permission.%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'430',%20'123',%20%22http://www.whfreeman.com%22);http://disporigimg%28%223711/pierce_14_10_FULL.jpg%22,%20%22Splicing%20of%20pre-mRNA%20requires%20consensus%20sequences.%22,%20%22Y%22,%20%22Figure%208%22,%20%221224097819597-5346069765_8%22,%20'Y',%20%22Used%20with%20permission.%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'430',%20'123',%20%22http://www.whfreeman.com%22);http://disporigimg%28%2234549/pierce_14_5_FULL.jpg%22,%20%22Three%20primary%20regions%20of%20mature%20mRNA%20are%20the%205'%20untranslated%20region,%20the%20protein-coding%20region,%20and%20the%203'%20untranslated%20region.%22,%20%22Y%22,%20%22Figure%206%22,%20%221224097786278-3025169620_6%22,%20'N',%20%22Used%20with%20permission.%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'739',%20'258',%20%22http://www.whfreeman.com%22);http://disporigimg%28%2234549/pierce_14_5_FULL.jpg%22,%20%22Three%20primary%20regions%20of%20mature%20mRNA%20are%20the%205'%20untranslated%20region,%20the%20protein-coding%20region,%20and%20the%203'%20untranslated%20region.%22,%20%22Y%22,%20%22Figure%206%22,%20%221224097786278-3025169620_6%22,%20'N',%20%22Used%20with%20permission.%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'739',%20'258',%20%22http://www.whfreeman.com%22);http://disporigimg%28%2234549/pierce_14_5_FULL.jpg%22,%20%22Three%20primary%20regions%20of%20mature%20mRNA%20are%20the%205'%20untranslated%20region,%20the%20protein-coding%20region,%20and%20the%203'%20untranslated%20region.%22,%20%22Y%22,%20%22Figure%206%22,%20%221224097786278-3025169620_6%22,%20'N',%20%22Used%20with%20permission.%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'739',%20'258',%20%22http://www.whfreeman.com%22);http://disporigimg%28%224421/pierce_table_13_2_FULL.jpg%22,%20%22Locations%20and%20functions%20of%20different%20classes%20of%20RNA%20molecules.%22,%20%22Y%22,%20%22Figure%205%22,%20%221224097772258-3181242700_5%22,%20'N',%20%22Used%20with%20permission.%20%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'455',%20'316',%20%22http://www.whfreeman.com%22);http://disporigimg%28%224421/pierce_table_13_2_FULL.jpg%22,%20%22Locations%20and%20functions%20of%20different%20classes%20of%20RNA%20molecules.%22,%20%22Y%22,%20%22Figure%205%22,%20%221224097772258-3181242700_5%22,%20'N',%20%22Used%20with%20permission.%20%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'455',%20'316',%20%22http://www.whfreeman.com%22);http://disporigimg%28%224421/pierce_table_13_2_FULL.jpg%22,%20%22Locations%20and%20functions%20of%20different%20classes%20of%20RNA%20molecules.%22,%20%22Y%22,%20%22Figure%205%22,%20%221224097772258-3181242700_5%22,%20'N',%20%22Used%20with%20permission.%20%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'455',%20'316',%20%22http://www.whfreeman.com%22);


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Figure 10

Outline | Keywords | Add Content to Group

Although the pairing between codon and anticodon takes place over three nucleotides, strict complementary base-pairing is only necessary between

the first two nucleotides. The third position is referred to as the "wobble" position (Figure 11), and the rules for base-pairing are less stringent at this

position. Because of this flexibility, the 30 to 40 tRNAs present in a cell can "read" all 61 codons in mRNA.

The opposite end of the folded structure, which is the 3' end of the tRNA, binds to its corresponding amino acidat an attachment site that is also

three nucleotides long, invariably CCA. Enzymes called aminoacyl-tRNA synthetases attach the correct amino acid to each tRNA, based on the

three-dimensional structure of the tRNAmolecule.

More and More RNAsFinally, there are still more forms of RNA beyond mRNA, rRNA, and tRNA. For instance, short RNAs are not only part of

organelles like ribosomes and spliceosomes, but also of some enzymes. For example, the enzymetelomerase, which adds

nucleotides to the ends of chromosomes, is composed of a 451-nucleotide RNA and several proteins. Juli Feigon at theUniversity of California, Los Angeles, together with postdoctoral scholar Carla Theimer and graduate student Craig Blois,

first solved the structure of an essential piece of this RNA by nuclear magnetic resonance spectroscopy (Theimer et al.,

2005). They revealed a unique RNA structure with extensive RNA folding, which is necessary for telomeraseactivity.

Other classes of RNAspeciesinclude microRNAs, small interfering RNAs, and sRNA-all of which are not translated into proteins but still perform

important functions in the cell. The discovery of these RNAs has been one of the most exciting advances in recent years, and there is currently a lot

of interest in the use of these molecules as possible therapies. But as far as their structure is concerned, these RNAs all share the same basic single-

stranded chemical structure with, in some cases, higher-order structures obtained through complementary base-pair folding.

From the RNA Tie Club to today, the more scientists have studied RNA, the more surprises they have uncovered. New functions for RNA, new

modifications to RNA, and other surprises undoubtedly await discovery in the years to come.

Figure 11: Wobble may exist in the pairing of a

codon on mRNA with an anticodon on tRNA.

The mRNA and tRNA pair in an antiparallel fashion.

Pairing at the first and second codon positions is in

accord with the Watson and Crick pairing rules (A

with U , G with C ) how ever, pairing rules are

relaxed at the third position of the codon, and G onthe anticodon can pair with either U or C on the

codon in this example.

Used with permission. 2005 by W. H.

Freeman and Company. All rights reserved.

References and Recommended Reading

Berget, S. M., Moore, C., & Sharp, P. A. Spliced segments at the 5' terminus of adenovirus 2 late mRNA. Proceedings of the National Academy of

Sciences74, 3171-3175 (1977)

Early, P., et al. Two mRNAs can be produced from a single immunoglobulin u chain by alternative RNS processing pathways. Cell20, 313-319

(1980)

Evans, R. M., et al. The initiation sites for RNA transcription in Ad2 DNA. Cell12, 733-739 (1977)

Holley, R. W., et al. Structure of a ribonucleic acid. Science147, 1462-1465 (1965) doi:10.1126/science.147.3664.1462

Patel, A. A., & Steitz, J. A. Splicing double: Insights from the second spliceosome. Nature4, 960-970 (2003) doi:10.1038/nrm1259 (link to article)

Pierce, B. A. Genetics: A Conceptual Approach, 2nd ed. (New York, Freeman, 2000)

Rich, A. A hybrid helix containing both deoxyribose and ribose polynucleotides and its relation to the transfer of information between the nucleic

acids. Proceedings of the National Academy of Sciences46, 1044-1053 (1960)

Rich, A., & Davies, D. R. A new two-stranded helical structure: Polyadenylic acid and polyuridylic acid.Journal of the American Chemical Society78,

3548-3549 (1956) (link to article)

Schmucker, D ., et al. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell101, 671-684 (2000)

Theimer, C. A., Blois, C. A., & Feigon, J. Structure of the human telomerase RNA pseudoknot reveals conserved tertiary interactions essential forfunction. Molecular C ell17, 671-682 (2005)
http://www.the-scientist.com/supplementary/flash/36975/RNApaper56.pdfhttp://www.nature.com/scitable/content/Splicing-double-insights-from-the-second-spliceosome-25641http://www.whfreeman.com/http://www.nature.com/scitable/topicpage/RNA-Functions-352http://www.nature.com/scitable/topicpage/RNA-Functions-352http://www.nature.com/scitable/topicpage/chemical-structure-of-rna-348#http://printreadingpage%28%29/http://www.nature.com/scitable/topicpage/chemical-structure-of-rna-348#http://www.facebook.com/share.php?u=http://twitter.com/share?url=https://plus.google.com/share?url=http://www.nature.com/scitable/topicpage/chemical-structure-of-rna-348#http://www.reddit.com/submit?url=http://www.nature.com/scitable/topicpage/chemical-structure-of-rna-348#http://www.nature.com/scitable/topicpage/chemical-structure-of-rna-348#http://www.nature.com/scitable/topicpage/chemical-structure-of-rna-348#urlhttp://www.nature.com/scitable/topicpage/chemical-structure-of-rna-348#TB_inline?height=300&width=400&inlineId=trOutLinehttp://disporigimg%28%223800/pierce_14_22_FULL.jpg%22,%20%22All%20tRNAs%20possess%20a%20common%20secondary%20structure,%20the%20cloverleaf%20structure.%22,%20%22Y%22,%20%22Figure%2010%22,%20%221224097872215-1136316078_10%22,%20'Y',%20%22Used%20with%20permission.%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'782',%20'353',%20%22www.whfreeman.com%22);http://disporigimg%28%223800/pierce_14_22_FULL.jpg%22,%20%22All%20tRNAs%20possess%20a%20common%20secondary%20structure,%20the%20cloverleaf%20structure.%22,%20%22Y%22,%20%22Figure%2010%22,%20%221224097872215-1136316078_10%22,%20'Y',%20%22Used%20with%20permission.%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'782',%20'353',%20%22www.whfreeman.com%22);http://disporigimg%28%223800/pierce_14_22_FULL.jpg%22,%20%22All%20tRNAs%20possess%20a%20common%20secondary%20structure,%20the%20cloverleaf%20structure.%22,%20%22Y%22,%20%22Figure%2010%22,%20%221224097872215-1136316078_10%22,%20'Y',%20%22Used%20with%20permission.%20%C2%A9%202005%20by%20W.%20H.%20Freeman%20and%20Company.%20All%20rights%20reserved.%22,%20'782',%20'353',%20%22www.whfreeman.com%22);


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