History of RNA biology

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Numerous key discoveries in biology have emerged from studies of RNA (ribonucleic acid), including seminal work in the fields of biochemistry, genetics, microbiology, molecular biology, molecular evolution, and structural biology. As of 2010, 30 scientists have been awarded Nobel Prizes for experimental work that includes studies of RNA. Specific discoveries of high biological significance are discussed in this article.

For related information, see the articles on History of molecular biology and History of genetics. For background information, see the articles on RNA and nucleic acids.

1930–1950

RNA and DNA have distinct chemical properties

When first studied in the early 1900s, the chemical and biological differences between RNA and DNA were not apparent, and they were named after the materials from which they were isolated; RNA was initially known as "

sugars, whereupon the common name for RNA became "ribose nucleic acid". Other early biochemical studies showed that RNA was readily broken down at high pH, while DNA was stable (although denatured) in alkali. Nucleoside composition analysis showed first that RNA contained similar nucleobases to DNA, with uracil instead of thymine, and that RNA contained a number of minor nucleobase components, e.g. small amounts of pseudouridine and dimethylguanine.[2]

Localization in cell and morphogenetic role

In 1933, while studying virgin sea urchin eggs, Jean Brachet suggested that DNA is found in cell nucleus and that RNA is present exclusively in the cytoplasm. At the time, "yeast nucleic acid" (RNA) was thought to occur only in plants, while "thymus nucleic acid" (DNA) only in animals. The latter was thought to be a tetramer, with the function of buffering cellular pH.[3][4] During the 1930s, Joachim Hämmerling conducted experiments with Acetabularia in which he began to distinguish the contributions of the nucleus and the cytoplasm substances (later discovered to be DNA and mRNA, respectively) to cell morphogenesis and development.[5][6]

1951–1965

Messenger RNA (mRNA) carries genetic information that directs protein synthesis

The concept of messenger RNA emerged during the late 1950s, and is associated with

bacteriophage T4 were instrumental in defining the nature of both messenger RNA and the genetic code. The short-lived nature of bacterial RNAs, together with the highly complex nature of the cellular mRNA population, made the biochemical isolation of mRNA very challenging. This problem was overcome in the 1960s by the use of reticulocytes in vertebrates,[7] which produce large quantities of mRNA that are highly enriched in RNA encoding alpha- and beta-globin (the two major protein chains of hemoglobin).[8] The first direct experimental evidence for the existence of mRNA was provided by such a hemoglobin synthesizing system.[9]

Ribosomes make proteins

In the 1950s, results of labeling experiments in rat liver showed that radioactive

Polysomes (multiple ribosomes moving along a single mRNA molecule) were identified in the early 1960s, and their study led to an understanding of how ribosomes proceed to read the mRNA in a 5′ to 3′ direction,[10] processively generating proteins as they do so.[11]

Transfer RNA (tRNA) is the physical link between RNA and protein

Biochemical fractionation experiments showed that radioactive amino acids were rapidly incorporated into small RNA molecules that remained soluble under conditions where larger RNA-containing particles would precipitate. These molecules were termed soluble (sRNA) and were later renamed transfer RNA (

codons.[12]

The genetic code is solved

The

codons). Today, our understanding of the genetic code permits the prediction of the amino sequence of the protein products of the tens of thousands of genes whose sequences are being determined in genome studies.[13]

RNA polymerase is purified

The biochemical purification and characterization of

transcription, and how those processes are regulated to regulate gene expression (i.e. turn genes on and off). Following the isolation of E. coli RNA polymerase, the three RNA polymerases of the eukaryotic nucleus were identified, as well as those associated with viruses and organelles. Studies of transcription also led to the identification of many protein factors that influence transcription, including repressors, activators and enhancers. The availability of purified preparations of RNA polymerase permitted investigators to develop a wide range of novel methods for studying RNA in the test tube, and led directly to many of the subsequent key discoveries in RNA biology.[14]

1966–1975

First complete nucleotide sequence of a biological nucleic acid molecule

Although determining the sequence of proteins was becoming somewhat routine, methods for sequencing of nucleic acids were not available until the mid-1960s. In this seminal work, a specific tRNA was purified in substantial quantities, and then sliced into overlapping fragments using a variety of ribonucleases. Analysis of the detailed nucleotide composition of each fragment provided the information necessary to deduce the sequence of the tRNA. Today, the sequence analysis of much larger nucleic acid molecules is highly automated and enormously faster.[15]

Evolutionary variation of homologous RNA sequences reveals folding patterns

Additional tRNA molecules were purified and sequenced. The first comparative sequence analysis was done and revealed that the sequences varied through evolution in such a way that all of the tRNAs could fold into very similar secondary structures (two-dimensional structures) and had identical sequences at numerous positions (e.g. CCA at the 3′ end). The radial four-arm structure of tRNA molecules is termed the 'cloverleaf structure', and results from the evolution of sequences with common ancestry and common biological function. Since the discovery of the tRNA cloverleaf, comparative analysis of numerous other homologous RNA molecules has led to the identification of common sequences and folding patterns.[16]

First complete genomic nucleotide sequence

The 3569 nucleotide sequence of all of the genes of the RNA

MS2 was determined by a large team of researchers over several years, and was reported in a series of scientific papers. These results enabled the analysis of the first complete genome, albeit an extremely tiny one by modern standards. Several surprising features were identified, including genes that partially overlap one another and the first clues that different organisms might have slightly different codon usage patterns.[17]

Reverse transcriptase can copy RNA into DNA

Retroviruses were shown to have a single-stranded RNA genome and to replicate via a DNA intermediate, the reverse of the usual DNA-to-RNA transcription pathway. They encode a RNA-dependent DNA polymerase (reverse transcriptase) that is essential for this process. Some retroviruses can cause diseases, including several that are associated with cancer, and HIV-1 which causes AIDS. Reverse transcriptase has been widely used as an experimental tool for the analysis of RNA molecules in the laboratory, in particular the conversion of RNA molecules into DNA prior to molecular cloning and/or polymerase chain reaction (PCR).[18]

RNA replicons evolve rapidly

Biochemical and genetic analyses showed that the enzyme systems that replicate viral RNA molecules (reverse transcriptases and RNA replicases) lack molecular proofreading (3′ to 5′ exonuclease) activity, and that RNA sequences do not benefit from extensive repair systems analogous to those that exist for maintaining and repairing DNA sequences. Consequently, RNA genomes appear to be subject to significantly higher mutation rates than DNA genomes. For example, mutations in HIV-1 that lead to the emergence of viral mutants that are insensitive to antiviral drugs are common, and constitute a major clinical challenge.[19]

Ribosomal RNA (rRNA) sequences provide a record of the evolutionary history of all life forms

Analysis of

eukaryotes.[20]

Non-encoded nucleotides are added to the ends of RNA molecules

Molecular analysis of mRNA molecules showed that, following transcription, mRNAs have non-DNA-encoded nucleotides added to both their 5′ and 3′ ends (guanosine caps and poly-A, respectively). Enzymes were also identified that add and maintain the universal CCA sequence on the 3′ end of tRNA molecules. These events are among the first discovered examples of

RNA processing, a complex series of reactions that are needed to convert RNA primary transcripts into biologically active RNA molecules.[21]

1976–1985

Small RNA molecules are abundant in the eukaryotic nucleus

RNA processing reactions within the nucleus and nucleolus, including RNA splicing, polyadenylation, and the maturation of ribosomal RNAs.[22]

RNA molecules require a specific, complex three-dimensional structure for activity

The detailed three-dimensional structure of

riboswitches and ribosomal RNA) also fold into specific structures containing a variety of 3D structural motifs. The ability of RNA molecules to adopt specific tertiary structures is essential for their biological activity, and results from the single-stranded nature of RNA. In many ways, RNA folding is more highly analogous to the folding of proteins rather than to the highly repetitive folded structure of the DNA double helix.[12]

Genes are commonly interrupted by introns that must be removed by RNA splicing

Analysis of mature eukaryotic

exons). Introns were shown to be removed after transcription through a process termed RNA splicing. Splicing of RNA transcripts requires a highly precise and coordinated sequence of molecular events, consisting of (a) definition of boundaries between exons and introns, (b) RNA strand cleavage at exactly those sites, and (c) covalent linking (ligation) of the RNA exons in the correct order. The discovery of discontinuous genes and RNA splicing was entirely unexpected by the community of RNA biologists, and stands as one of the most shocking findings in molecular biology research.[23]

Alternative pre-mRNA splicing generates multiple proteins from a single gene

The great majority of protein-coding genes encoded within the nucleus of

isoforms that can exhibit a variety of (usually related) biological functions. Indeed, most of the proteins encoded by the human genome are generated by alternative splicing.[24]

Discovery of catalytic RNA (ribozymes)

An experimental system was developed in which an intron-containing rRNA precursor from the nucleus of the ciliated protozoan

enzymes.[25][26]

RNA was likely critical for prebiotic evolution

The discovery of catalytic RNA (

last common ancestor.[27]

Introns can be mobile genetic elements

Some self-splicing introns can spread through a population of organisms by "homing", inserting copies of themselves into genes at sites that previously lacked an intron. Because they are self-splicing (that is, they remove themselves at the RNA level from genes into which they have inserted), these sequences represent

group I or group II families of self-splicing introns.[28]

Spliceosomes mediate nuclear pre-mRNA splicing

Introns are removed from nuclear pre-mRNAs by

snRNA and protein molecules whose composition and molecular interactions change during the course of the RNA splicing reactions. Spliceosomes assemble on and around splice sites (the boundaries between introns and exons in the unspliced pre-mRNA) in mRNA precursors and use RNA-RNA interactions to identify critical nucleotide sequences and, probably, to catalyze the splicing reactions. Nuclear pre-mRNA introns and spliceosome-associated snRNAs show similar structural features to self-splicing group II introns. In addition, the splicing pathway of nuclear pre-mRNA introns and group II introns shares a similar reaction pathway. These similarities have led to the hypothesis that these molecules may share a common ancestor.[29]

1986–2000

RNA sequences can be edited within cells

Messenger RNA precursors from a wide range of organisms can be edited before being translated into protein. In this process, non-encoded nucleotides may be inserted into specific sites in the RNA, and encoded nucleotides may be removed or replaced. RNA editing was first discovered within the mitochondria of kinetoplastid protozoans, where it has been shown to be extensive.[30] For example, some protein-coding genes encode fewer than 50% of the nucleotides found within the mature, translated mRNA. Other RNA editing events are found in mammals, plants, bacteria and viruses. These latter editing events involve fewer nucleotide modifications, insertions and deletions than the events within kinetoplast DNA, but still have high biological significance for gene expression and its regulation.[31]

Telomerase uses a built-in RNA template to maintain chromosome ends

Telomerase is an enzyme that is present in all eukaryotic nuclei which serves to maintain the ends of the linear DNA in the linear

template strand, and a protein component that has reverse transcriptase activity and adds nucleotides to the chromosome ends using the internal RNA template.[32]

Ribosomal RNA catalyzes peptide bond formation

For years, scientists had worked to identify which protein(s) within the

last common ancestor of all known forms of life.[33]

Combinatorial selection of RNA molecules enables in vitro evolution

Experimental methods were invented that allowed investigators to use large, diverse populations of RNA molecules to carry out in vitro molecular experiments that utilized powerful selective replication strategies used by geneticists, and which amount to evolution in the test tube. These experiments have been described using different names, the most common of which are "combinatorial selection", "in vitro selection", and SELEX (for

Systematic Evolution of Ligands by Exponential Enrichment). These experiments have been used for isolating RNA molecules with a wide range of properties, from binding to particular proteins, to catalyzing particular reactions, to binding low molecular weight organic ligands. They have equal applicability to elucidating interactions and mechanisms that are known properties of naturally occurring RNA molecules to isolating RNA molecules with biochemical properties that are not known in nature. In developing in vitro selection technology for RNA, laboratory systems for synthesizing complex populations of RNA molecules were established, and used in conjunction with the selection of molecules with user-specified biochemical activities, and in vitro schemes for RNA replication. These steps can be viewed as (a) mutation, (b) selection, and (c) replication. Together, then, these three processes enable in vitro molecular evolution.[34]

2001 – present

Many mobile DNA elements use an RNA intermediate

Transposable genetic elements (transposons) are found which can replicate via transcription into an RNA intermediate which is subsequently converted to DNA by reverse transcriptase. These sequences, many of which are likely related to retroviruses, constitute much of the DNA of the eukaryotic nucleus, especially so in plants. Genomic sequencing shows that retrotransposons make up 36% of the human genome and over half of the genome of major cereal crops (wheat and maize).[35]

Riboswitches bind cellular metabolites and control gene expression

Segments of RNA, typically embedded within the 5′-untranslated region of a vast number of bacterial mRNA molecules, have a profound effect on gene expression through a previously-undiscovered mechanism that does not involve the participation of proteins. In many cases, riboswitches change their folded structure in response to environmental conditions (e.g. ambient temperature or concentrations of specific metabolites), and the structural change controls the translation or stability of the mRNA in which the riboswitch is embedded. In this way, gene expression can be dramatically regulated at the post-transcriptional level.[36]

Small RNA molecules regulate gene expression by post-transcriptional gene silencing

Another previously unknown mechanism by which RNA molecules are involved in genetic regulation was discovered in the 1990s. Small RNA molecules termed microRNA (miRNA) and small interfering RNA (siRNA) are abundant in eukaryotic cells and exert post-transcriptional control over mRNA expression. They function by binding to specific sites within the mRNA and inducing cleavage of the mRNA via a specific silencing-associated RNA degradation pathway.[37]

Noncoding RNA controls epigenetic phenomena

In addition to their well-established roles in translation and splicing, members of

Xist (X-inactive-specific-transcript) is essential for X-chromosome inactivation in mammals.[38]

Nobel Laureates in RNA biology

See also: List of RNA biologists
Name Dates Awards
Altman, Sidney born 1939 1989 Nobel Prize in Chemistry
Baltimore, David born 1938 1975 Nobel Prize in Physiology or Medicine
Barré-Sinoussi, Françoise born 1947 2008 Nobel Prize in Physiology or Medicine
Blackburn, Elizabeth born 1948 2009 Nobel Prize in Physiology or Medicine
Brenner, Sydney born 1927 2002 Nobel Prize in Physiology or Medicine
Cech, Thomas born 1947 1989 Nobel Prize in Chemistry
Charpentier, Emmanuelle born 1968 2020 Nobel Prize in Chemistry
Crick, Francis 1916–2004 1962 Nobel Prize in Physiology or Medicine
Doudna, Jennifer born 1964 2020 Nobel Prize in Chemistry
Dulbecco, Renato 1914–2012 1975 Nobel Prize in Physiology or Medicine
Fire, Andrew born 1959 2006 Nobel Prize in Physiology or Medicine
Gilbert, Walter born 1932 1980 Nobel Prize in Chemistry
Greider, Carol born 1961 2009 Nobel Prize in Physiology or Medicine
Holley, Robert 1922–1993 1968 Nobel Prize in Physiology or Medicine
Jacob, François 1920–2013 1965 Nobel Prize in Physiology or Medicine
Khorana, H. Gobind 1922–2011 1968 Nobel Prize in Physiology or Medicine
Klug, Aaron born 1926 1982 Nobel Prize in Chemistry
Kornberg, Roger born 1947 2006 Nobel Prize in Chemistry
Mello, Craig born 1960 2006 Nobel Prize in Physiology or Medicine
Monod, Jacques 1910–1976 1965 Nobel Prize in Physiology or Medicine
Montagnier, Luc born 1932 2008 Nobel Prize in Physiology or Medicine
Nirenberg, Marshall 1927–2010 1968 Nobel Prize in Physiology or Medicine
Ochoa, Severo 1905–1993 1959 Nobel Prize in Physiology or Medicine
Temin, Howard
 1934–1994 1975 Nobel Prize in Physiology or Medicine
Ramakrishnan, Venkatraman
 born 1952 2009 Nobel Prize in Chemistry
Roberts, Richard born 1943 1993 Nobel Prize in Physiology or Medicine
Sharp, Philip
 born 1944 1993 Nobel Prize in Physiology or Medicine
Steitz, Thomas 1940–2018 2009 Nobel Prize in Chemistry
Szostak, Jack born 1952 2009 Nobel Prize in Physiology or Medicine
Todd, Alexander
 1907–1997 1957 Nobel Prize in Chemistry
Watson, James
 born 1928 1962 Nobel Prize in Physiology or Medicine
Wilkins, Maurice 1916–2004 1962 Nobel Prize in Physiology or Medicine
Yonath, Ada born 1939 2009 Nobel Prize in Chemistry

References

  1. Oxford Reference
    . Retrieved on 21 October 2015.
  2. doi:10.1146/annurev.bi.10.070141.001253
    .
  3. ^ Brachet, J. (1933). "Recherches sur la synthese de l'acide thymonucleique pendant le developpement de l'oeuf d'Oursin" [Research on the synthesis of thymonucleic acid during the development of the sea urchin egg]. Archives de Biologie (in French). 44: 519–576.
  4. ^ Burian, R. (1994). "Jean Brachet's Cytochemical Embryology: Connections with the Renovation of Biology in France?" (PDF). In Debru, C.; Gayon, J.; Picard, J.-F. (eds.). Les sciences biologiques et médicales en France 1920–1950. Cahiers pour I'histoire de la recherche. Vol. 2. Paris: CNRS Editions. pp. 207–220.
  5. ISBN 978-0-12-364302-5
    .
  6. ISBN 978-0-12-364586-9
    .
  7. PMID 16590302
    .
  8. PMID 4896247
    .
  9. PMID 13758530
    .
  10. PMID 5339691
    .
  11. PMID 5329473
    .
  12. ^
    PMID 60910
    .
  13. PMID 5322508
    .
  14. PMID 5001045
    .
  15. PMID 4875713
    .
  16. PMID 6163215
    .
  17. S2CID 4289674
    .
  18. PMID 9759480
    .
  19. S2CID 10753127
    .
  20. PMID 10900003
    .
  21. PMID 1353951
    .
  22. PMID 6180681
    .
  23. PMID 2880558
    .
  24. PMID 3304142
    .
  25. PMID 2197983
    .
  26. PMID 9759486
    .
  27. S2CID 31040875
    .
  28. PMID 8352597
    .
  29. PMID 8811184
    .
  30. PMID 2470509
    .
  31. PMID 11092837
    .
  32. PMID 16756500
    .
  33. PMID 1604315
    .
  34. PMID 11539574
    .
  35. PMID 18680436
    .
  36. PMID 19298181
    .
  37. PMID 19239886
    .
  38. PMID 21030644
    .
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