Central dogma of molecular biology
The central dogma of molecular biology describes the flow of genetic information within a biological system, primarily detailing how DNA is transcribed into RNA and then translated into proteins. Initially proposed by Francis Crick in 1958, this concept established a unidirectional pathway: DNA to RNA (via transcription) and RNA to protein (via translation). However, subsequent discoveries have revealed complexities that modify this original perspective. For instance, retroviruses, like HIV, utilize reverse transcription, a process where RNA is converted back into DNA, challenging the linearity of the original dogma.
Additionally, RNA has been found to possess the ability to self-replicate, further complicating the narrative. The discovery of ribozymes—RNA molecules that can catalyze their own processing—highlights the functional versatility of RNA beyond mere intermediaries. Recent studies also question the simplicity of the relationship between gene expression and protein production, suggesting that the central dogma may need further refinement. Understanding these processes is critical for grasping the mechanisms behind various biological functions and diseases, making the central dogma a foundational principle in molecular genetics.
Central dogma of molecular biology
SIGNIFICANCE: The central dogma states precisely how DNA is processed to produce proteins. Originally thought to be a unidirectional process proceeding from DNA to RNA and then to protein, it is now known to include reverse transcription and the enzymatic activity of certain RNA molecules. The central dogma lies at the core of molecular genetics, and understanding it, and particularly reverse transcription, is key to comprehending both the way viruses cause disease and methods that have revolutionized 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 was read in the ribosome, and the appropriate amino acids carried by transfer RNAs (tRNAs) were assembled into protein according to the 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 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 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 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 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 sequence. RNA processing thus demonstrates another needed modification of the central dogma: The colinearity of gene and protein in prokaryotes predicts that 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.
In 2023, research findings once again caused scientists to raise questions about the central dogma. University of California, Los Angeles researchers working with mesenchymal stem cells, which are found in bone marrow, attempted to encourage the secretion of a protein growth factor called VEGF-A. They tested the assumption that higher gene expression in the stem cells would lead to higher levels of VEGF-A, but the correlation between gene expression and growth factor expression was weak. This led the researchers to suggest the central dogma may need to be revised.
Importance and Applications
The theoretical importance of the 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 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
- codonthree nucleotides in DNA or RNA that correspond with a particular amino acid or stop signal
- colinearitythe exact correspondence between DNA or RNA codons and a protein amino acid sequence
- complementary basesthe 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)
- exonthe part of the coding sequence of mRNA that specifies the amino acid sequence of a protein
- hydrogen bonda weak chemical bond that forms between atoms of hydrogen and atoms of other elements, including oxygen and nitrogen
- introna noncoding intervening sequence present in many eukaryotic genes that is transcribed but removed before translation
- retrovirusa virus that carries reverse transcriptase that converts its RNA genome into a DNA copy that integrates into the host chromosome
- reverse transcriptionthe conversion of RNA into DNA catalyzed by the enzyme reverse transcriptase
- ribozymecatalytic RNA
- subunita polypeptide chain of a protein
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