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I'm thinking of the human genome specifically, but more general answers are welcome.

As RNA polymerase moves along the DNA helix it follows a single strand. The two DNA strands are unwound locally by a helicase enzyme. However, after some distance, I imagine that either the polymerase must move around the axis of the DNA OR the DNA must somehow be rotated along it's length to relieve the twisting by the polymerase.

I can't quite understand how the DNA is free to rotate, being part of a very long molecule. However the other option is also causing me a problem: the growing (nascent) mRNA can be tens of thousands of bases long while still attached to the RNA polymerase and the DNA template. If the RNA polymerase follows the helix of the DNA, does it also drag the full transcript around with it?

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  • $\begingroup$ My bounty is prompted by watching this WEHI animation, where the first sequence ignores the need for rotation and shows both the RNA polymerase and the DNA as lacking any rotation. The second sequence shows the DNA as spinning and the RNA polymerase as static. Is the second sequence accurate or also an approximation of reality? How does the DNA accommodate tens of thousands of revolutions required for long sequences? $\endgroup$
    – RomanSt
    Commented Mar 31, 2020 at 2:35
  • $\begingroup$ I'm not sure the question makes much sense. Whether an object is 'rotating' or not, needs to be discussed in relation to a common frame of reference or to another object. An enzyme (like a polymerase) is much smaller than a chromosome, by many orders of magnitude. The DNA is flexible, of course, and requires bending, twisting, and other local configuration changes to function. But, again, a chromosome is a huge molecule! Is like asking if a passenger (polymerase) is moving, or if it's the train (chromosome) what is moving. Clearly both are moving, but at different temporal and spatial scales. $\endgroup$
    – TumbiSapichu
    Commented Apr 4, 2020 at 4:10
  • $\begingroup$ @TumbiSapichu the bottom line is that the RNA polymerase must rotate with respect to the DNA. The obvious frame of reference is the solvent they are both suspended in. If the polymerase rotates w.r.t. the solvent then the RNA that it outputs will end up wound around the DNA - is it? If not, then the polymerase must have been stationary and the DNA was the one rotating w.r.t. the solvent. The question is which is it, and if it's the latter, how does the DNA accommodate such twisting, being a very long molecule. $\endgroup$
    – RomanSt
    Commented Apr 4, 2020 at 13:23

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Both the DNA and the RNA polymerase complexes moves along the DNA molecule like it was a track. While the new mRNA is big, it would never be as big as the whole genome, so the reference point is the DNA molecule. Plus, the functioning of the movement of this enzymes is quite similar to other proteins that move "climbing" long polymers, such as actin polymers or microtubules.

One of the theoretical models that describes the movement of this kind of proteins is the model of rectified thermal diffusion, based on Richard Feynman's idea of the Brownian ratchet. A Brownian ratchet is a device that allows the conversion of Brownian random movements into a directional force.

http://en.wikipedia.org/wiki/Brownian_ratchet

The polymerases consume ATP, which enable them to suffer cyclic conformational changes (one change per ATP consumed), which allows the complex to attach to the molecule and detach. Once the complex has detached, by simple diffusion it moves in a random direction. Then, it attaches again. If the movement has occurred in the right sense, it will stay where it ended, while if it has gone in the wrong sense it will return to its previous position. As only a few movements are allowed, the complex will only move in that sense, even if the motor force is random.

I don't know exactly what conformational changes occurs in the RNA polymerase, but this general process seems to apply to almost any motile protein, including those enzymes that travel across polymers. Since the motor force is simple diffusion, and since the mRNA molecule doesn't need to "travel" with the polymerase (it just floats joined to it, but doesn't "pull"), I think there isn't any trouble with this.

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    $\begingroup$ I'm thinking more of the topology of strands of RNA and DNA. What happens to the mRNA/DNA as the polymerase moves around the spiral of the DNA? $\endgroup$
    – Dave Gerrard
    Commented Aug 29, 2013 at 13:05
  • $\begingroup$ mRNA are single-stranded, so they don't have problems with supercoiling. RNA polymerase complex carry helicase and topoisomerase activity in order to relax the DNA, because it needs to separate both strands of the DNA and because the movement changes the coiling in the DNA, as they cause positive supercoiling in front of the enzime and negative supercoiling behind. The wikipedia article is pretty good: en.wikipedia.org/wiki/RNA_polymerase $\endgroup$
    – Miguel Ángel Naranjo Ortiz
    Commented Aug 29, 2013 at 13:27
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    $\begingroup$ I think he is asking a different question. At some point the RNA should be wound around the DNA if the RNAP is spinning around the DNA. $\endgroup$
    – bobthejoe
    Commented Sep 6, 2013 at 10:09
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The partial answer by Miguel helped a lot but I needed to go and read about the extra part that I was missing: Topoisomerases.

The DNA is unwound beneath the RNA polymerase, which causes supercoiling in front and behind. For long transcripts to proceed, the current theory is that the DNA template has to be cut, unwound and re-ligated and that this is performed by Topoisomerases.

This raises the questions as to how often the DNA gets cut and re-ligated during active transcription and does this produce a noticeable effect (i.e. mutation)?

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There is an alternative view that polymerases are sort of DNA motors that move DNA while they themselves remain static. I cannot find that reference now but I read this ~5 years back in a Nature Reviews article. The notion of transcription and replication factories also fits this model.

Highly transcribed regions do have a higher propensity to acquire mutations [1].

Although I am not sure about it but sequence composition of genes might also have a role. The pitch of the helix along with other physical parameters are dependent on sequence composition. It has been shown that geneic regions have different composition compared to non-transcribed regions (geneic regions have higher GC content [2].

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I would have to agree that the "transcription factories" (several RNA Polymerases and some other proteins combined) attract DNA and transcription factors, and then start transcription while they remain static. One such factory can actually transcribe many genes at once. Most books and online sources still describe the Polymerase as moving along the DNA and carrying out transcription, but this has been proven wrong. source: http://www.ncbi.nlm.nih.gov/pubmed/8799830

can't find the article on Nature either, but I heard about it too.

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