Central dogma of molecular biology

The central dogma of molecular biology was first enunciated by Francis Crick in 1958 and re-stated in a Nature paper published in 1970:

The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid.

In other words, 'once information gets into protein, it can't flow back to nucleic acid.'

The central dogma is often misunderstood. It is frequently confused with the standard pathway of information flow from "DNA to RNA to protein". There are notable exceptions to the normal pathway of information flow and these are often mistakenly referred to as exceptions to the central dogma.

The standard information flow pathway can be summarized in a very short and oversimplified manner as "DNA makes RNA makes proteins, which in turn facilitate the previous two steps as well as the replication of DNA", or simply "DNA → RNA → protein". This process is therefore broken down into three steps: transcription, translation, and replication. By new knowledge of the RNA processing, a fourth step must be included: splicing.

Transcription

Transcription is the process by which the information contained in a section of DNA is transferred to a newly assembled piece of messenger RNA (mRNA). It is facilitated by RNA polymerase and transcription factors.

Splicing

In eukaryote cells the primary transcript (pre-mRNA) is processed. One or more sequences (introns) are cut out. The mechanism of alternative splicing makes it possible to produce different mature mRNA molecules, depending on what sequences are treated as introns and what remain as exons. However, not all living cells have mRNA that undergoes splicing; splicing is absent in prokaryotes.

Translation

Eventually, this mature mRNA finds its way to a ribosome, where it is translated. In prokaryotic cells, which have no nuclear compartment, the process of transcription and translation may be linked together. In eukaryotic cells, the site of transcription (the cell nucleus) is usually separated from the site of translation (the cytoplasm), so the mRNA must be transported out of the nucleus into the cytoplasm, where it can be bound by ribosomes. The mRNA is read by the ribosome as triplet codons, usually beginning with an AUG, or initiator methonine codon downstream of the ribosome binding site. Complexes of initiation factors and elongation factors bring aminoacylated transfer RNAs (tRNAs) into the ribosome-mRNA complex, matching the codon in the mRNA to the anti-codon in the tRNA, thereby adding the correct amino acid in the sequence encoding the gene. As the amino acids are linked into the growing peptide chain, they begin folding into the correct conformation. This folding continues until the nascent polypeptide chains are released from the ribosome as a mature protein. In some cases the new polypeptide chain requires additional processing to make a mature protein. The correct folding process is quite complex and may require other proteins, called chaperone proteins. Occasionally proteins themselves can be further spliced, when this happens the inside "discarded" section is known as an intein.

Replication

Finally, as the final step in the Central Dogma, to transmit the genetic information between parents and progeny, the DNA must be replicated faithfully. Replication is carried out by a complex group of proteins that unwind the superhelix, unwind the double-stranded DNA helix, and, using DNA polymerase and its associated proteins, copy or replicate the master template itself so the cycle can repeat DNA → RNA → protein in a new generation of cells or organisms.

Alterations to the central dogma

In his 1970 paper on the subject, Crick pointed out that the central dogma, while useful as a theory to guide experiment, was not to be taken as dogma:

"Although the details of the classification proposed here are plausible, our knowledge of molecular biology, even in one cell -- let alone for all the organisms in nature -- is still far too incomplete to allow us to assert dogmatically that it is correct." - Francis Crick

Since the 1970 paper, a number of facts have emerged suggesting the need for it to be restated:

Flow from RNA to DNA

After the central dogma was expounded, retroviruses were discovered. These transcribe RNA into DNA through the use of a special enzyme called reverse transcriptase. This confirmed that the flow RNA → DNA does occur. Initially, this was thought to occur only in viruses, but, more recently, examples of RNA to DNA flow have been shown in higher animals, including humans. Example of this are retrotransposons.

Viruses with RNA-only genomes

Some virus species have their entire genome encoded in the form of RNA. Thus, their information flow consists only of RNA → Protein

Non-coding RNAs

Many RNAs in an organism achieve a functional state capable of affecting the phenotype of the organism without ever being translated into a protein. These RNAs include rRNAs, ribozymes, tRNAs, miRNAs, snoRNAs, and siRNAs.

Prions

Prions are proteins that propagate themselves by making conformational changes in other molecules of the same type of protein. This change affects the behaviour of the protein. In fungi this change can be passed from one generation to the next, i.e. Protein → Protein. This is not considered an exception to the central dogma since the sequence of the protein is unchanged.

Criticisms of the use of the central dogma as a research strategy

Some researchers in the area of systems biology claim that scientists sometimes misuse the central dogma as a research strategy. They claim that an uncritical reading of the central dogma could inhibit novel approaches to understanding multicellular development of organisms as well as multicellular diseases; that the central dogma is often used as a reductionist research strategy that proceeds bottom up, attempting to explain all biological phenomena in molecular terms. Although they don't dispute the very specific reading of the central dogma, these researchers claim that a reductionist research strategy may limit the understanding of complex systems that cannot be analyzed by their molecular interactions alone because of the combinatorial complexity involved (Werner 2005).

References

1958 Crick, F.H.C., On Protein Synthesis. in Symp. Soc. Exp. Biol. XII, 139-163. (pdf, early draft of original article)
1970 Crick, F., Central Dogma of Molecular Biology. Nature 227, 561-563.
2005 Werner, E., Genome Semantics, In Silico Multicellular Systems and the Central Dogma, FEBS Letters 579, pp 1779-1782 (March 21, 2005).

External links

Central Dogma : Article from Knowmed Article Repository: A history of the development of the dogma, listing a few key experiments

Molecular biology | Molecular genetics

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