What is the central dogma of molecular biology?

Original Central Dogma

Nobel Prize winner Francis Crick, who was codiscoverer with James Watson of the double helical structure of DNA, coined the term “central dogma” in 1958 to describe the fact that the processing of genetic information contained in DNA proceeded unidirectionally by its conversion first to an RNA copy, called messenger RNA (mRNA), in a molecular process called transcription. Then the genetic information contained in the sequence of bases in the mRNA was read in the ribosome, and the appropriate amino acids carried by transfer RNAs (tRNAs) were assembled into protein according to the genetic code in a process called translation. The basis of these reactions stemmed from the properties of DNA, particularly its double helical structure. The fact that the two strands of DNA were held together by hydrogen bonds between specific nucleic acid bases (guanine-cytosine, adenine-thymine) on the two strands clearly suggested how the molecule could be duplicated. Watson and Crick postulated that if they split the double-stranded structure at the hydrogen bonds, attached new complementary bases, and reformed the hydrogen bonds, precise copies identical to the original DNA would result. In an analogous manner, RNA was produced by using one DNA strand as a template and adding the correct complementary bases according to what came to be called Watson Crick base pairing. Thus the original dogma stated that transfer of genetic information proceeded unidirectionally, that is, only from DNA to RNA to protein. The only exception was the duplication of DNA in a process called replication.

Modified Central Dogma

Several discoveries made it necessary to change the central dogma. The first and most heretical information came from the study of retroviruses, including the human immunodeficiency virus (HIV). Howard Temin reported that viruses of this group contained an enzyme called reverse transcriptase, which was capable of converting RNA to DNA and thus challenging the whole basis of molecular reactions and the central dogma. Temin and David Baltimore were subsequently awarded Nobel Prizes for their work describing this new enzyme. They were able to show that it synthesizes a DNA strand complementary to the RNA template, and then the DNA-RNA hybrid is converted to a DNA-DNA molecule, which inserts into the host chromosome. Only then can transcription and translation take place.

The second significant change was finding that RNA can act as a template for its own synthesis. This situation occurs in RNA bacteriophages such as MS2 and QB. These phages are very simple, with genomes specifying only three proteins, a coat and attachment proteins and an RNA replicase subunit. This subunit combines with three host proteins to form the mature RNA replicase that catalyzes the replication of the single-stranded RNA. Thus translation to form the protein subunit of RNA replicase occurs using the RNA genome as mRNA upon viral infection without transcription taking place. Only then is the RNA template successfully replicated.

The third natural modification of the original dogma also concerned the properties of RNA. Thomas Cech, in 1982, discovered that introns could be spliced out of eukaryotic genes without proteins catalyzing the process. For the discovery and characterization of catalytic RNA, Cech and Sidney Altman were awarded Nobel Prizes for their work in 1989. Their experiments demonstrated that RNA introns, also called ribozymes, had enzymatic activity that could produce a functional mRNA. This process occurred by excising the introns and combining the exons, thus restoring colinearity of DNA and amino acid sequence. RNA processing thus demonstrates another needed modification of the central dogma: The colinearity of gene and protein in prokaryotes predicts that gene expression results directly from the sequence of bases in its DNA. In the case of eukaryotic genes with multiple introns, however, colinearity does not result until the RNA processing has taken place. Therefore, the correspondence of the codons in the original DNA sequence containing the introns does not correspond to the order of amino acids in the protein product.

Numerous examples also exist of DNA rearrangements occurring before final gene expression takes place. Examples include the formation of antibodies, the expression of different mating types in yeast, and the expression of different surface antigens in parasites, such as the trypanosome protozoan parasite, which causes sleeping sickness. All of these gene products are produced as a result of gene rearrangements, and the original DNA sequences are not colinear with the amino acid sequences in the protein.

Importance and Applications

The theoretical importance of the central dogma is unquestioned. For example, one modern-day scourge, the human immunodeficiency virus(HIV), replicates its genetic material by reverse transcription (central dogma modification), and one of the drugs shown to contain this virus, azidothymidine (AZT), targets the reverse transcriptase enzyme. Perhaps even more important is the use of the reverse transcription polymerase chain reaction (RT-PCR), one application of the polymerase chain reaction originally devised in 1983 by Kary B. Mullis, formerly of Cetus Corporation. RT-PCR employs reverse transcriptase to form a double-stranded molecule from RNA, resulting in a revolutionary technique that can generate usable amounts of DNA from extremely small quantities of DNA or from poor-quality DNA. Also of practical importance is the laboratory modification of hammerhead ribozymes (central dogma modification), found naturally in plant pathogens, for clinical uses, such as to target RNA viruses infecting patients, including HIV and papillomavirus.

Key terms



codon

:

three nucleotides in DNA or RNA that correspond with a particular amino acid or stop signal




colinearity

:

the exact correspondence between DNA or RNA codons and a protein amino acid sequence




complementary bases

:

the nucleic acid bases in different strands of nucleic acid in RNA and DNA that pair together through hydrogen bonds: guanine-cytosine and adenine-thymine (in DNA and RNA) and adenine-uracil (in RNA)




exon

:

the part of the coding sequence of mRNA that specifies the amino acid sequence of a protein




hydrogen bond

:

a weak chemical bond that forms between atoms of hydrogen and atoms of other elements, including oxygen and nitrogen




intron

:

a noncoding intervening sequence present in many eukaryotic genes that is transcribed but removed before translation





retrovirus


:

a virus that carries reverse transcriptase that converts its RNA genome into a DNA copy that integrates into the host chromosome




reverse transcription

:

the conversion of RNA into DNA catalyzed by the enzyme reverse transcriptase




ribozyme

:

catalytic RNA




subunit

:

a polypeptide chain of a protein





Bibliography

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Cech, T. R. “RNA as an Enzyme.” Scientific American 255.5 (1986): 64–75. Print.

Crick, F. “Central Dogma of Molecular Biology.” Nature 8 Aug. 1970: 561–63. Print.

de Lorenzo, Victor. "From the Selfish Gene to Selfish Metabolism: Revisiting the Central Dogma." BioEssays 36.3 (2014): 226–35. Print.

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