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 RNA Tie 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 involving gene regulation in the model organism Caenorhabditis elegans. The members of this club, each nicknamed for a particular amino acid, exchanged letters in which they presented various unpublished ideas in an attempt to understand the structure of RNA and how this molecule participates in the building of proteins. During the following 50 years, many questions were answered and many surprises were uncovered.
![The chemical structures of DNA (left) and RNA (right).](javascript:dispOrigImg("/scitable/content/ne0000/ne0000/ne0000/ne0000/117909638/101995_59.jpg", "The chemical structures of DNA (left) and RNA (right).", "true", "Figure 1", "In double-stranded DNA, two hydrogen bonds connect the nucleotides thymine (T) to adenine (A); three hydrogen bonds connect the nucleotides guanine (G) to cytosine (C). The sugar-phosphate backbones (grey) run anti-parallel to each other, so that the 3’ and 5’ ends of the two strands are aligned. RNA is usually single-stranded. In DNA, the sugar that composes the sugar-phosphate backbone is deoxyribose; in RNA, the sugar is ribose. The nucleotide thymine (T) is not present in RNA: rather than binding with thymine, the nitrogenous base adenine (A) base-pairs with the nitrogenous base uracil (U) in RNA.", "true", "All rights reserved.", '700', '616', 'http://www.nature.com/scitable');)
Figure 1 Early Discoveries of RNA Structure
Today, researchers know that cells contain a variety of forms of RNA—including messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA)—and each form is involved in different functions and activities. Messenger RNA is 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 polypeptide chain 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 protein and rRNA.
![The primary and secondary structures of RNA.](javascript:dispOrigImg("/scitable/content/ne0000/ne0000/ne0000/ne0000/117909775/105312_60.jpg", "The primary and secondary structures of RNA.", "true", "Figure 2", "(A) A region of single-stranded RNA. The sugar component of the sugar-phosphate backbone is ribose: a five carbon sugar with a hydroxyl group on its 2’ carbon atom. The sugar component of the sugar-phosphate backbone in DNA is deoxyribose: a five carbon sugar with a hydrogen atom, instead of a hydroxyl group, on its 2’ carbon atom. Additionally, RNA does not contain the nitrogenous base thymine (T), found in DNA. Instead, the nitrogenous base uracil (U), not found in DNA, binds with the base adenine. (B) The primary and secondary structures of RNA. The primary structure refers to the molecule’s nucleotide sequence; the secondary structure refers to its three-dimensional conformation after folding has occurred.", "true", "All rights reserved.", '700', '1043', 'http://www.nature.com/scitable');)
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, RNA is 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, uracil can 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 RNA Tie 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 DNA molecule could form a hybrid double helix was the first experimental demonstration of a way in which information could be transferred from DNA to RNA (Rich, 1960).
![Maturation and architecture of tRNA](javascript:dispOrigImg("/scitable/content/ne0000/ne0000/ne0000/ne0000/101825/nrmicro1491-i1_FULL.jpg", "Maturation and architecture of tRNA", "true", "Figure 3", "The global organization of the tRNA structure is highly conserved in all forms of life. Prominent features of the tRNA structure, as shown in the figure, include: an acceptor stem with the CCA trinucleotide at the 3' end (the site of aminoacylation and trans-peptidation reactions in the protein-biosynthesis cycle); a D loop (named after a tandem dihydrouridine modification, labelled \"D\" in the figure, which is commonly found in this loop); an anticodon loop that includes the anticodon, which is a nucleotide triplet responsible for recognition of a coding triplet in mRNA, and the T loop, named after the highly conserved triplet. Filled circles represent nucleotides that are not usually modified; open circles represent commonly modified nucleotides other than D, T and psi.", "true", "All rights reserved.", '255', '285', 'http://www.nature.com');)
Single-stranded RNA can also form many secondary structures in which a single RNA molecule folds over and forms hairpin loops, 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 mRNA during translation (Figure 3).
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 acid strand. 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 mRNA molecule would code for which amino acids.
