CAT tails weaken the central dogma – why it matters and why it doesn’t

By Matthew Cobb

One of the closest things to a purely biological law is a hypothesis Francis Crick outlined in 1957, which he called ‘the central dogma’ of genetics. This refers to potential transfer of genetic information in our cells, and states, among other things, that

. . . once information (meaning here the determination of a sequence of units) has been passed into a protein molecule it cannot get out again, either to form a copy of the molecule or to affect the blueprint of a nucleic acid.

In its full form, Crick’s hypothesis was that information can get out of DNA into RNA to determine the structure of a protein, but proteins cannot specify the sequence of new proteins, and the information in proteins cannot make the reverse journey back into your genes – your DNA cannot be rewritten by a protein. (This idea – often called ‘epigenetics’ – has been dealt with many times here.)

The central dogma has been the focus of repeated criticism over the past sixty years, partly because of the discovery of new facts, and partly because the unfortunate term ‘dogma’ tends to be a lightning rod for debate (Crick later said ‘the use of the word dogma caused almost more trouble than it was worth’ – he coined the term without realising its full implications).

In a paper that appeared in this week’s issue of Science, researchers from a variety of US laboratories, led by Jonathan Weissman and Adam Frost of UCSF and Onn Brandman from Stanford, have chipped away at one part of the central dogma, which states that a protein cannot determine the amino acid sequence of another protein. They have discovered that in very unusual circumstances, a protein can indeed determine the sequence of amino acids, by adding two particular amino acids, Alanine and Threonine to one end (the ‘C’ terminal) of a protein that is being synthesised, but which for some reason has ‘stalled’.

These happily-named CAT tails (you can work out why they are called this from the previous sentence) may mark defective proteins (they are only partially complete, because biosynthesis has stalled) so they can be disposed, or they may enable cells to identify the cellular structures – ribosomes – that have caused the stalling, and which may themselves be defective. So they form part of the cell’s housekeeping functions, and are not part of most examples of protein synthesis.

The exact detail of the paper is pretty heavy biochemistry – I don’t claim to understand it all – so I’ll focus on the most striking issue, which the authors surprisingly don’t mention at all.

This research shows that, strictly speaking, Crick was wrong. In these extremely unusual conditions (they emphasise this repeatedly in the paper), a set of molecules called the ribosome quality control complex (RQC), intervene to add the CAT tails. This involves a protein called Rqc2p recruiting transfer RNA (tRNA) molecules that gather Alanine and Threonine respectively. Up until now, it was thought that only messenger RNA could recruit tRNA molecules to add ‘information’ to a protein, that is, adding amino acids (this is happening right now in every cell of your body).

On the one hand this discovery is fascinating, and it adds to our knowledge. On the other, it does not shake the foundations of biology, which is presumably why the authors did not cite Crick’s 1957 lecture or even mention the central dogma (maybe they tried to put their finding into the bigger picture and the reviewers complained – sadly Science is closed in more than one respect – unlike some open access journals like eLife, it does not publish the reviewers’ comments; we can discuss the advantages of this another time).

That having been said, normally the practice is to sex-up and exaggerate the significance of results, so we should be grateful to the authors for not trumpeting ‘central dogma reversed’ or some such. The truth, as always, is more interesting than hype.

In 1970, following the discovery of reverse transcriptase, an enzyme that enables RNA viruses to copy themselves into DNA (so carrying out the allegedly impossible information transfer RNA→ DNA), Crick felt obliged to explain exactly what he had originally meant by the central dogma. As he had made clear in 1957, this was not actually a dogma – something that could not be questioned – it was a hypothesis based on current knowledge. Crick had in fact said that the pathway RNA→ DNA was possible, but he had no evidence for it and could see no biological function for it.

In his 1970 clarification, Crick highlighted three information transfers that he postulated would never occur: protein → protein, protein → DNA and protein → RNA. However, even as he made such a clear prediction, Crick was cautious, underlining our ignorance and the fragility of the evidence upon which he based his slightly revised ‘dogma’:

our knowledge of molecular biology, even in one cell – let alone for all organisms in nature – is still far too incomplete to allow us to assert dogmatically that it is correct.

And he went on to highlight one potential exception, the disease “scrapie”, which we now know involves pathological prion proteins altering the shape of normal prion proteins, with devastating results (this is also the basis of ‘mad cow disease’ and its human equivalent, variant Creuzfeld-Jacob Disease).

In both the benign and the pathogenic forms of the prion, the amino acid sequence remains the same, so there is no transfer of information as defined by the central dogma. Although three-dimensional conformation is a form of information – indeed, Crick accepted as much – the change induced by the prion protein is probably more similar to the action of a crystal growing by assembling identical copies of itself. There are similar effects whereby chaperone proteins allow proteins to correctly fold themselves in our cells, thereby facilitating the expression of the sequence information into three dimensions.

The new results on the behaviour of Rqc2p allow no such wiggle-room, however. These findings show that under very particular circumstances, a protein can change the amino acid sequence of another protein by adding information, something that Crick was confident could not happen.

However, in the grand scheme of things, this doesn’t really matter as it is clear that this is an extremely unusual case. The vast majority of protein synthesis events involve the classic information flow DNA → RNA → protein. Despite this striking and odd example, the central dogma remains intact as a description of how our cells function. This is just one more of those pesky things that biology revels in, but which physics abhors – an exception.

This relaxed attitude, which I share with the vast majority of biologists, underlines a difference between general statements or hypotheses in biology and axioms or laws in mathematics or physics. Exceptions to the central dogma – even a solid example of information flowing directly from protein → DNA, which has still not been found – would only radically revise how genetics and evolution work if they took place systematically and on a wide scale.

The example of CAT tails encoded by proteins does not challenge our key understanding. It is fascinating, and it may open the road to new biotechnological tools. But virtually all of our existing results and experimental protocols emerge unscathed, because they function perfectly well in the absence of this additional mode of information transfer.

The reason that scientists accept the central dogma is not because it is a dogma but because the evidence supports it. When new evidence arises, then, as the French phrase puts it: Il n’y a que les imbéciles qui ne changent pas d’avis – only fools do not change their mind.

*****

You can read more about the central dogma, its place in our understanding of how biology works, and recent challenges to it, in my forthcoming book Life’s Greatest Secret: The Race to Crack the Genetic Code, to be published this summer by Profile (UK) and Basic Books (USA).

*****

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Reference ($$$): Shen PS, Park J, Qin Y, Li X, Parsawar K, Larson MH, Cox J, Cheng Y, Lambowitz AM, Weissman JS, Brandman O, Frost A. (2015) Protein synthesis. Rqc2p and 60S ribosomal subunits mediate mRNA-independent elongation of nascent chains. Science 347:75-8.

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36 Comments

  1. merilee
    Posted January 5, 2015 at 10:05 am | Permalink

    meow

  2. ROBIN CORNWELL
    Posted January 5, 2015 at 10:14 am | Permalink

    Terrific explanation – thank you! There is something elegant about breaking through widely held ideas in science. That is, indeed, the triumph of science. I do wonder if the choice of ‘CAT’ was more than just the first letter and a tongue in cheek way of acknowledging Crick’s misfortunate choice of the word ‘d*gma’.

    • Posted January 5, 2015 at 10:26 am | Permalink

      Oh yes! Maybe you have something!

    • Walt Jones
      Posted January 5, 2015 at 11:15 am | Permalink

      “Dogma” always brings to my mind a bumper sticker I once saw:

      “My karma ran over your dogma.”

      • Posted January 5, 2015 at 11:20 am | Permalink

        …whilst the dogma was chasing a stigma….

        b&

        • merilee
          Posted January 5, 2015 at 1:04 pm | Permalink

          and the Sigma brought them all together again;-)

          • Diane G.
            Posted January 9, 2015 at 6:03 pm | Permalink

            Buh da bum!

        • Mike Cracraft
          Posted January 5, 2015 at 2:35 pm | Permalink

          “Any stigma is good enough to beat a dogma with.”

    • Torbjörn Larsson, OM
      Posted January 5, 2015 at 12:41 pm | Permalink

      I haven’t read the papers, but Larry Moran’s quotes of Crick’s texts make me thing that he wanted to point out that the Sequence Hypothesis was weaker than the Central Dogma. The SH was weaker in scope (more potential pathways) and as it is (at least) now apparent in rigidity. (The SH is Watson’s hypothesis of (DNA ->) RNA -> protein, which is often mistaken for the CD.)

      The Sequence Hypothesis and the Central Dogma in 1957

      “My own thinking (and that of many of my colleagues) is based on two general principles, which I shall call the Sequence Hypothesis and the Central Dogma. The direct evidence for both of them is negligible, but I have found them to be of great help in getting to grips with these very complex problems. I present them here in the hope that others can make similar use of them. Their speculative nature is emphasized by their names. It is an instructive exercise to attempt to build a useful theory without using them. One generally ends in the wilderness.

      The Sequence Hypothesis. This has already been referred to a number of times. In its simplest form it assumes that the specificity of a piece of nucleic acid is expressed solely by the sequence of its bases, and that this sequence is a (simple) code for the amino acid sequence of a particular protein.

      This hypothesis appears to be rather widely held. Its virtue is that it unites several remarkable pairs of generalizations: the central biochemical importance of proteins and the dominating role of genes, and in particular of their nucleic acid; the linearity of protein molecules (considered covalently) and the genetic linearity within the functional gene, as shown by the work of Benzer and Pontecorvo; the simplicity of the composition of protein molecules and the simplicity of nucleic acids. Work is actively proceeding in several laboratories, including our own, in an attempt to provide more direct evidence for this hypothesis.

      The Central Dogma. This states that once “information” has passed into protein it cannot get out again. In more detail, the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid is impossible. Information means here the precise determination of sequence, either of bases in the nucleic acid or of amino acid residues in the protein.”

      Crick, F.H.C. (1958) On protein synthesis. Symp. Soc. Exp. Biol. XII:138-163 quoted in Judson, H.F. The Eight Day of Creation, Expanded Edition (1979, 1996) p. 332.”

      [ http://sandwalk.blogspot.se/2007/01/central-dogma-of-molecular-biology.html ]

      • Mark Sturtevant
        Posted January 5, 2015 at 2:02 pm | Permalink

        That is interesting. It appears, if I am understanding it right, that what we often call the CD (DNARNA–>protein) is really the SH. Is that right?

        • Josephine
          Posted January 6, 2015 at 7:22 am | Permalink

          Yes

  3. Posted January 5, 2015 at 10:25 am | Permalink

    “The exact detail of the paper is pretty heavy biochemistry – I don’t claim to understand it all” – thank goodness in a way – I thought you were setting us extra homework!

    Very interesting – thanks for explaining.

    • Posted January 5, 2015 at 10:29 am | Permalink

      …& Amazon UK says Matthew’s book is out on March 5th!

  4. Reginald Selkirk
    Posted January 5, 2015 at 10:27 am | Permalink

    I don’t get it, this seems overblown. Nonribosomal peptides have been known for quite some time. These were very direct examples of one protein influencing the sequence of another. The novelty of the current finding seems to be that the influence is being done through a ribosomal system.

    The current finding most certainly does not constitute a “reverse translation”, which is what it would take to overthrow the “Central Dogma”.
    Masayuki Nahimoto, J. Theor. Biol. (2001) 209, pp 181-187. doi:10.1006/jtbi.2000.2253

    • Delphin
      Posted January 5, 2015 at 10:43 am | Permalink

      I am not a biologist or chemist myself but this seems right to me. The “stalled” caveat suggests this is part of a repair mechanism doesn’t it?

      • Reginald Selkirk
        Posted January 5, 2015 at 11:13 am | Permalink

        I try to avoid teleology when I can. It could serve to help the ribosome spit out and mark for proteolysis stalled states, or it could be some sort of defense against viral genes.

    • Luis Servin
      Posted January 5, 2015 at 11:40 am | Permalink

      I agree that this finding does not go against the central dogma. This “repair” mechanism doesn’t alter the coding sequence for the proteins in the DNA, i.e. this change in the protein sequence information does not go back to the DNA.

    • Torbjörn Larsson, OM
      Posted January 5, 2015 at 12:28 pm | Permalink

      My thoughts too, as per my longer comment below.

  5. Posted January 5, 2015 at 10:31 am | Permalink

    Alas, Mr. Crick died a decade too soon to see this paper. I can only imagine how thrilled he’d have been to have read it.

    b&

  6. frankschmidtmissouri
    Posted January 5, 2015 at 11:45 am | Permalink

    Dreadful post, Matthew, although you are somewhat excused by admitting that you don’t know much Biochemistry. There are many examples of proteins altering the primary structure of another protein, or of themselves:

    – Inteins
    – Ubiquitination
    – Proline hydroxylation
    – Selenocysteine and its alternative elongation factor (very close to the situation described here, but on the internal part of a protein)
    – Protein cleavage (insulin, pituitary hormones, and the list goes on)

    All of these are at least as “profound” as the phenomenon above, which may be why the authors didn’t make the claim you think they could have.

    Sir Francis would have taken this “breakthrough” in stride.

    • Posted January 5, 2015 at 12:50 pm | Permalink

      Sorry you didn’t rate the post, Frank, though I’m not sure it’s “dreadful”. I wasn’t claiming that the central dogma was overthrown, and you are right that Crick – and you and I – wouldn’t have been worried. That was the point of the post, and why I spent some time explaining quite how rich Crick’s thinking was in the matter.

      This finding is different from the examples you give because it’s a protein that directly recruits tRNAs and adds amino acid residues to a protein, so information is being added (of course loads of enzymes cleave proteins and so therefore affect primary structure – that is rather different, not what Crick had in mind, and not what the post was about).

      As I understand it (poorly, I admit), the addition of selenocysteine into proteins involves a less direct intervention of a protein into the sequence of amino acids than this example.

      You might think this finding is uninteresting, but I predict that some philosophers of biology will get very excited by this, for the wrong reasons. I was simply trying to describe the result and to put it (and the central dogma) into context.

      Thanks to you and the other critical posters for your comments – they will be very useful to me, as I have to compose a brief few sentences about this to add as footnote to my book. Comments on WEIT have been extremely helpful over the last 18 months as I’ve tried out arguments here (especially the ones that pick me up for misteaks), and you are collectively acknowledged in the book for that.

      Matthew

      • Peter Ellis
        Posted January 6, 2015 at 4:15 am | Permalink

        There’s a key point you’re missing, which is that while Rqc2p does indeed recruit tRNAs and add amino acids to the stalled protein on the ribosome, it does not add them in any specific order. It adds a random mix of the two amino acids.

        Thus, although amino acids are being added, there is no sequence information being added.

        This distinction between the biochemistry of the molecular events and the underlying logic of the information flow is the whole point of the central dogma.

        • Peter Ellis
          Posted January 6, 2015 at 4:25 am | Permalink

          Put another way, if you took two identically-stalled ribosomes with the same nascent peptide on each, and let Rqc2p do its thing to both of them, you would get two fundamentally different final peptides back at the end of the process. The CAT tails would not be the same, there is no sequence information there.

      • Josephine
        Posted January 6, 2015 at 7:25 am | Permalink

        As always, Larry Moran has an excellent review on the issue (and many more) on his blog (if you haven’t seen it): http://sandwalk.blogspot.co.uk/2015/01/thinking-critically-about-central-dogma.html

        • W.Benson
          Posted January 6, 2015 at 10:01 am | Permalink

          Always? Larry Moran is excellent when explaining molecular biology and the role of drift in genome evolution. When he traipses into adaptive evolution, not so good.

        • ratabago
          Posted January 6, 2015 at 8:27 pm | Permalink

          Larry Moran also has a follow up to the press release about the CAT paper, with a reference to Matthew’s post: http://sandwalk.blogspot.com.au/2015/01/the-textbooks-are-wrong-about-protein.html

          There is an interesting question by Rosie Redfield in the comments:

          “Is this the first example of non-templated synthesis of an amino-acid chain by the ribosomal protein synthesis machinery?”

    • Keith Cook or more
      Posted January 5, 2015 at 3:21 pm | Permalink

      Interesting post, I enjoyed the refresher on this aspect of biology.. thanks.

    • Hempenstein
      Posted January 5, 2015 at 4:40 pm | Permalink

      Well, inteins are still translated components that (IIRC) autocatalytically excise themselves in a sequence-dependent manner, and ubiquitinylation and Pro hydroxylation are post-translational modifications that take place on the translated product. From the description here (haven’t read the paper yet) this can also be taken as yet another post-translational modification, but it also appears to be a first example of adding one or more amino acids to the main chain.

  7. pacopicopiedra
    Posted January 5, 2015 at 11:50 am | Permalink

    That was a very long and roundabout way of plugging your book;) Just kidding. Thanks for this interesting post, and your book sounds very good, too. I will have to add it to my long list of books to read.

  8. Torbjörn Larsson, OM
    Posted January 5, 2015 at 12:25 pm | Permalink

    I wouldn’t worry too much about differences in laws between biology and physics. (Mathematics is explicitly rule-building, so is an exception all by itself. =D)

    First, there is a lot of empirical laws on complex systems that have similar exceptions, say how low pressure water ices are lighter than their liquid.

    Second, statistical physics and more generally quantum physics show that classical laws (regularities) must have exceptions, say the uncertainty principle.

    For what it is worth, here was my layman reaction the other day:

    “Before the incomplete protein is recycled, Rqc2 prompts the ribosomes to add just two amino acids (of a total of 20) – alanine and threonine – over and over, and in any order.”

    So it doesn’t break Crick’s Central Dogma, that sequence information put into a protein does not make it out again.

    It looks more like evolution saw a handy signal: “… the nonsensical sequence likely serves specific purposes. The code could signal that the partial protein must be destroyed, or it could be part of a test to see whether the ribosome is working properly.”

    [Quotes from the press release.]

  9. DTaylor
    Posted January 5, 2015 at 1:47 pm | Permalink

    Very interesting post, and I look forward to your book. The clarity of your writing is much admired and appreciated.

  10. madscientist
    Posted January 5, 2015 at 2:58 pm | Permalink

    It’s a pity we can’t ask Crick. On the other hand if it’s only a single acid added to the terminus and the partially assembled protein is then destroyed rather than continuing assembly, I wouldn’t count it against Crick’s idea since this is a pathway for disposal of a partially assembled protein and not part of the pathway of a complete assembly – that is, the protein is not contributing to the assembly of a useful protein. So the non-dogmatic dogma may need a little revision, but like Darwin’s thesis it’s not dead yet.

  11. Posted January 5, 2015 at 4:02 pm | Permalink

    Don’t prions figure into regular CJD? The only difference between CJD and nvCJD, in my understanding, is that CJD arises naturally through mutation whereas nvCJD arrives from an outside source, something akin to poisoning, if you will.


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