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Theoretically, is it possible to obtain the original gene from the protein’s amino acid sequence as its “template”, as in, the reverse of how gene’s codons were “templates” for the amino acid sequence of the protein? I’m curious to know if it’s possible to use enzymes such as reverse transcriptase to obtain DNA from a protein in a reversed central dogma model.

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  • $\begingroup$ What do you mean by "theoretical"? As in could a cell do it if it wanted to, or if they are even capable of doing so? Or do you mean can we realistically envision the chemistry that would be requires for that to happen? $\endgroup$ – Cell Aug 7 '18 at 0:21
  • $\begingroup$ This can be answered in both senses, which are very interesting. $\endgroup$ – Adam Radek Martinez Aug 7 '18 at 0:24
  • $\begingroup$ I say “theoretically” because I am not sure if it has been done before, and I am not sure if that is because of the practical impossibility of the idea. Therefore, I guess what I mean is the last phrase you proposed. $\endgroup$ – P. SN Aug 7 '18 at 1:02
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    $\begingroup$ what kind of googling have you done? Have you heard of protein sequencing? $\endgroup$ – aaaaaa Aug 7 '18 at 16:09
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Let’s first consider what the Central Dogma[1] actually says. It is precisely summarised in the following figure[2]:

central dogma

solid arrows represent transfer of information that has been observed directly; dashed arrows represent potential, not yet observed, transfer of information

In the time since the original formulation of the Central Dogma in 1958, we have been able to contribute evidence for one of the dashed lines: RNA→DNA is performed in vivo via reverse transcriptase. By contrast, note the absence of any arrows originating from “protein”. The idea of the Central Dogma was that proteins were an information transfer sink: information could only flow in, not out.

And Crick and his contemporaries had good reasons for assuming such an information sink: translation from RNA to proteins is lossy because the genetic code is degenerate. A given amino acid can be encoded by more than one codon.

This doesn’t mean that polypeptide chains couldn’t be reverse translated into “a” RNA representation. But it wouldn’t necessarily be the original RNA. Stated like this, it’s obviously possible: we can in fact take a polypeptide chain, sequence it, and synthesise a corresponding RNA.

However, this doesn’t happen in nature — at least, it hasn’t been observed so far, and there are good reasons to assume it doesn’t happen at all. In fact, Crick’s paper[1] explains:

The transfer protein→RNA … would have required (back) translation, that is, the transfer from one alphabet to a structurally quite different one. It was realized that forward translation involved very complex machinery. Moreover, it seemed unlikely on general grounds that this machinery could easily work backwards. The only reasonable alternative was that the cell had evolved an entirely separate set of complicated machinery for back translation, and of this there was no trace, and no reason to believe that it might be needed.

The “complicated machinery” Crick mentions here consists of two distinct parts: On the one hand the ribosome, and on the other hand the aminoacyl tRNA synthetases (aaRSs, singular aaRS). The latter is essentially the physical embodiment of the genetic code in the cell. The former is the machinery necessary to decode RNAs using the codon adapters (= tRNAs) charged by the aaRSs.

Crick correctly notes that, in order to allow the transfer protein→RNA, the cell would require a system analogous to the ribosome and all the aaRSs, redundantly encoding the exact same information. And it would need to ensure that these two distinct encoding systems (translation and reverse translation) never get out of sync with each other.

It’s worth contemplating, briefly, why the cellular translation process isn’t simply reversible, given that it’s an chemical process, and thus pretty much by definition reversible in theory. The reason for this is that translation happens in two entirely distinct, and physically separate, stages: the charging of individual tRNAs with their corresponding amino acids by an aaRS, and the actual mRNA translation by the ribosome.

Simply reversing the ribosome activity would result in a polypeptide being digested from one end, yielding individual amino acids. However, the ribosome actually has no facility for capturing these amino acids, they would simply diffuse away without being attached to a tRNA, let alone the right tRNA. A successful reverse translation would have to physically couple each type of aaRS in turn to the ribosome to ensure that terminal amino acids would pair with the correct tRNA, which, in turn, would pair with a codon. There are two fundamental objections to it, which render it impossible:

  • Codons, which could be combined into mRNA chains, don’t swim around individually. In fact, short RNA chains are highly unstable and are quickly degraded. By contrast, individual ribonucleotides can be combined into chains — that’s what polymerases do all day, after all. But the ribosome doesn’t possess polymerase activity, and the tRNA anticodon would not provide sufficient physical support to enable a polymerase to dock to it and start synthesising a secondary strand.
  • Steric hindrance prevents the aaRS enzymes from interacting with the tRNAs while they are being held by the ribosome: the ribosome and the aaRSs would have to physically overlap.

It’s hard to get definitive answers in science purely from theoretical considerations, but this one’s as certain as you’re likely to get: cellular translation using the ribosome is a non-reversible process. Reverse translation, if it existed, would therefore require a separate machinery.

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    $\begingroup$ My answer explicitly omits the discussion of the transfer protein→protein, as this is a topic all of its own, and would increase the size of the answer unduly. $\endgroup$ – Konrad Rudolph Aug 7 '18 at 13:49
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Contrary to my belief, it may be possible.

The main concern we must look at is Protein to RNA, as we know RNA to DNA can be done through reverse transcription.

Some evolutionary scientist believe that reverse translation may be a process that could have occurred naturally during the process of evolution to create the central dogma we know today. Hence, there still lies the possibility that there is a mechanism for the process that remains undiscovered. Just because we do not have proof of it does not mean it does not exist.

There is also a product under development called PeplicaTM that claims to be able to convert protein to RNA, which can then be amplified with conventional PCR. Though, I can not find much information regarding it making me a little hesitant on suggesting whether it actually works.

The following is a little bit of a review on the topic that further outlines some points I mentioned. If you are interested, do read it.

https://www.omicsonline.org/open-access/revisiting-cricks-dogma-and-the-impossibility-of-reverse-translation-jtco.1000110.php?aid=24768

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  • $\begingroup$ +1 for finding that article, it’s certainly … interesting. And by that I may or may not actually mean that it’s absurd. At the very least it’s probably the most uncharitable treatment I’ve ever read of Crick’s work, and it provides an intellectually dishonest caricature of his arguments so that the author can dispatch them. $\endgroup$ – Konrad Rudolph Aug 7 '18 at 13:56
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The key underlying concept in Francis Crick’s so-called Central Dogma of Molecular Biology is that the genetic information to create a new cell (or organism) is encoded in a cell’s DNA, and therefore it is the DNA that gets replicated when a mother cell divides to give two daughter cells, and it is the same DNA that has to be equally partitioned, or transmitted, to each of the daughter cells for life to continue.

The primary information encoded in that DNA is the sequence of all of the proteins that the daughter cells might need to make to stay alive. And so we have:

”DNA makes RNA and RNA makes Protein”

Where the messenger RNA is a transient intermediary between where the genetic information is stored, and where the genetic information is decoded (on the ribosomes, where protein synthesis occurs).

Reversing the central dogma would be a situation where the proteins of a cell contain the genetic information that gets replicated in the mother cell and then gets partitioned, or transmitted to the two daughter cells. If proteins could be reverse translated into a genetic mRNA (this has certainly been done in a test tube where the primary sequence of a protein has been used to create an oligonucleotide primer (admittedly made of DNA) (this required a human who could read the universal genetic code table—also assembled by humans)), then in theory that RNA could be converted into a DNA copy by RT, as you described. But then we are left with an incomplete scenario where it is the DNA sequences which have to provide the enzymatic, structural, and regulatory roles of the resulting cells (i.e., all of the roles that proteins currently provide).

DNA does not possess any enzymatic activity (as far as we know), so at this point the model you propose does not seem viable.

You also are ignoring the fact that the genetic code is degenerate such that there are up to six different codons that can encode one of the 20 common amino acids, so any reverse-translatase would have to be imprecise.

Consider this question: where is the genetic code table stored inside a cell?

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    $\begingroup$ I think your answer erects a partial straw man: there’s no necessity in this model for DNA to have an active role: It could conceivably act as a passive intermediate molecule. This is in fact exactly what happens with retroviruses. $\endgroup$ – Konrad Rudolph Aug 7 '18 at 13:45
  • $\begingroup$ I think you make a valid point (straw man), and I like the thoroughness of your answer. I am thinking of deleting mine now. $\endgroup$ – mdperry Aug 7 '18 at 14:04

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