4 The central dogma: Replication and expression of genomes

A little history.  Who came up with the idea?

The central dogma of molecular biology is an explanation of the flow of genetic information within a biological system. It is often stated as “DNA makes RNA and RNA makes protein,” although this is not its original meaning. It was first stated by Francis Crick in 1957, then published in 1958:

and re-stated in a Nature paper published in 1970.

A second version of the central dogma is popular but not precisely correct. This is the simplistic DNA → RNA → protein pathway published by James Watson in the first edition of The Molecular Biology of the Gene (1965). Watson’s version differs from Crick’s because Watson describes a two-step (DNA → RNA and RNA → protein) process as the central dogma. While the dogma, as originally stated by Crick, remains valid today, Watson’s version does not.

Why is this idea so central?

The central dogma tells us how the codes of living organisms work.  The biopolymers that comprise DNA, RNA and proteins are linear polymers (each monomer is connected to at most two other monomers). The sequence of their monomers effectively encodes information. The transfers of information described by the central dogma ideally are faithful, deterministic transfers, wherein one biopolymer’s sequence is used as a template for the construction of another biopolymer with a sequence that is entirely dependent on the original biopolymer’s sequence.

The dogma is a framework for understanding the transfer of sequence information between information-carrying biopolymers, in the most common or general case, in living organisms. There are 3 major classes of such biopolymers: DNA and RNA (both nucleic acids), and protein. There are 3×3=9 conceivable direct transfers of information that can occur between these. The dogma classes these into 3 groups of 3: three general transfers (believed to occur normally in most cells), three special transfers (known to occur, but only under specific conditions in case of some viruses or in a laboratory), and three unknown transfers (believed never to occur). The general transfers describe the normal flow of biological information: DNA can be copied to DNA (DNA replication), DNA information can be copied into mRNA (transcription), and proteins can be synthesized using the information in mRNA as a template (translation). The special transfers describe: RNA being copied from RNA (RNA replication), DNA being synthesised using an RNA template (reverse transcription), and proteins being synthesised directly from a DNA template without the use of mRNA. The unknown transfers describe: a protein being copied from a protein, synthesis of RNA using the primary structure of a protein as a template, and DNA synthesis using the primary structure of a protein as a template – these are not thought to naturally occur.

The observed paths of information flow in living cells

Central Dogma of Molecular Biology with MachineryThe figure to the right sketches out the central dogma of molecular biology.  The main directions of information flow in living cells are indicated by arrows (replication, transcription and translation). The main molecular machines involved in those stages are named (DNA polymerase, RNA polymerase, and the ribosome).

Replication

In the sense that DNA replication must occur if genetic material is to be provided for the progeny of any cell, whether somatic or reproductive, the copying from DNA to DNA arguably is the fundamental step in the central dogma. A complex assembly called the replication fork is where the action takes place in going from the parent strand to the complementary daughter strand.

The replication fork (in bacteria) includes:

  • a helicase that unwinds the superhelix as well as the double-stranded DNA helix to create the replication fork
  • SSB protein that binds open the double-stranded DNA to prevent it from reassociating
  • RNA primase that adds a complementary RNA primer to each template strand as a starting point for replication
  • DNA polymerase III that reads the existing template chain from its 3′ end to its 5′ end and adds new complementary nucleotides from the 5′ end to the 3′ end of the daughter chain
  • DNA polymerase I that removes the RNA primers and replaces them with DNA
  • DNA ligase that joins the two Okazaki fragments with phosphodiester bonds to produce a continuous chain

Transcription

Transcription is the process by which the information contained in a section of DNA is replicated in the form of a newly assembled piece of messenger RNA (mRNA). Enzymes facilitating the process include RNA polymerase and transcription factors. In eukaryotic cells the primary transcript is pre-mRNA. Pre-mRNA must be processed for translation to proceed. Processing includes the addition of a 5′ cap and a poly-A tail to the pre-mRNA chain, followed by splicing. Alternative splicing occurs when appropriate, increasing the diversity of the proteins that any single mRNA can produce. The product of the entire transcription process (that began with the production of the pre-mRNA chain) is a mature mRNA chain.

Translation

The mature mRNA finds its way to a ribosome, where it gets translated. In prokaryotic cells, which have no nuclear compartment, the processes of transcription and translation may be linked together without clear separation. 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 ribosome reads the mRNA triplet codons, usually beginning with an AUG (adenine−uracil−guanine), or initiator methionine 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 on the tRNA. Each tRNA bears the appropriate amino acid residue to add to the polypeptide chain being synthesised. As the amino acids get linked into the growing peptide chain, the chain begins folding into the correct conformation. Translation ends with a stop codon which may be a UAA, UGA, or UAG triplet.

The mRNA does not contain all the information for specifying the nature of the mature protein. The nascent polypeptide chain released from the ribosome commonly requires additional processing before the final product emerges. For one thing, the correct folding process is complex and vitally important. For most proteins it requires other chaperone proteins to control the form of the product. Some proteins then excise internal segments from their own peptide chains, splicing the free ends that border the gap; in such processes the inside “discarded” sections are called inteins. Other proteins must be split into multiple sections without splicing. Some polypeptide chains need to be cross-linked, and others must be attached to non-protein molecules such as heme before they become functional.

Special information flows

Special transfers of information are highlighted in green in the above figure, including reverse transcription and RNA replication

Reverse transcription is the transfer of information from RNA to DNA (the reverse of normal transcription). This is known to occur in the case of retroviruses, such as HIV, as well as in eukaryotes, in the case of retrotransposons and telomere synthesis. It is the process by which genetic information from RNA gets transcribed into new DNA.

RNA replication

RNA replication is the copying of one RNA to another. Many viruses replicate this way. The enzymes that copy RNA to new RNA, called RNA-dependent RNA polymerases, are also found in many eukaryotes where they are involved in RNA silencing.[8]

RNA editing, in which an RNA sequence is altered by a complex of proteins and a “guide RNA”, could also be seen as an RNA-to-RNA transfer.

References and online resource

Animation: Central Dogma of Biology

Animation: DNA Replication

Animation: Transcription of RNA

Animation: mRNA Splicing

Animation: Protein Translation

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An Introduction to Molecular Biology by Philip McFadden is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License, except where otherwise noted.

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