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This is a long one. (TLDR at the bottom)

The prospect of alternative genetic polymers has attracted the interest of people for almost as long as we have known about DNA. Indeed, many alternative polymers have already been found, with comparable properties to DNA (some of which are mentioned here). The one I will focus on today is PNA.

Peptide Nucleic Acid (which really should be called Peptide Nucleic Polymer, since the peptide backbone is not really an acid) has a number of interesting properties when used in conjunction with DNA.

  • It is more chemically stable than the DNA backbone.
  • It forms a more stable duplex with DNA i.e the melting temperature (which is the temperature at which the two strands of the duplex fall apart) for a DNA-DNA duplex is 10°C, while for a PNA-DNA duplex it is 31°C.
  • PNA-DNA duplexes are more intolerant of base mismatches. A mismatched base pair will cause the duplex to become more unstable than a DNA-DNA duplex or even a PNA-PNA duplex (Refer to this article for more details, scroll down to the discussion section for a quick summary).

How is this relevant to us, you say?

Well, imagine a hypothetical cell containing a PNA-DNA duplex as the genetic polymer. This cell would have a number of advantages over more conventional cells.

  • It would have a genetic data storage polymer that is more resistant to oxidative and hydrolysis damage. The PNA backbone of the duplex is more chemically stable and more hydrophobic than the DNA backbone. So in the event of damage to the DNA, the repair enzymes can use the PNA side to reconstitute the DNA side.
  • The heteroduplex is more intolerant of base mismatch, to the extent of structure destabilization, which means that error correction enzymes will have an easier time to get to and correct such mistakes.
  • It gets rid of the weirdness of DNA replication.

The last one requires a bit more explanation. Refer to this webpage, this Wikipedia article and this video for more details, but the short version is that new nucleotides can only be added to the DNA in the 5' to 3' direction. This causes speedy replication of the leading strand, but the lagging strand has to contend with stuff like Okazaki fragments and multiple extra enzymes to be replicated successfully. Not to mention that all the extra time spent unwound from a duplex creates a higher chance of introducing mutations to the strand.

However, a PNA backbone will have no such requirements. The N-(2-aminoethyl)-glycine monomer is the basic building block of the PNA backbone, and it can be extended in any direction with the right enzyme, which can be a ribosome like enzyme, maybe? Since they are quite good at creating peptide polymers, aka proteins, and has the benefit of already existing. Let's call it a PNA polymerase.

So in this genetic polymer replication system,

  1. There will be two distinct replication enzymes. One is PNA polymerase, which will use the DNA strand as a template. The other is DNA polymerase, which will use the PNA strand as a template.
  2. The leading strand will be the PNA backbone, and the DNA polymerase will assemble the DNA backbone like it normally and quickly does (in the 5' to 3' direction).
  3. The lagging strand will be the DNA backbone, and here the PNA polymerase will build the PNA backbone like assembling a protein.

There will be no looping strands, no Okazaki fragments, no extra enzymes to deal with all the weirdness of the lagging strand. I'm guessing this will lead to a major simplification of the replication machinery complex, as well as improving replication speed, efficiency and accuracy.

Sounds wonderful, right? I think so too. But as it happens, I'm not a biochemist and I have the tendency to skip out on crucial details in pursuit of the perfect solution. That's where you guys come in, to give me a (pseudo?) reality check. Does my idea have merit or is it completely fanciful? Any input will be appreciated. Thanks!

TLDR: a hypothetical PNA-DNA duplex as a genetic polymer would be superior to our regular DNA duplex in terms of stability, damage resistance, error correction and replication efficiency.

Baron_vonCernogratz
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  • It'd be more energetically favorable to make it likely that fossils of ancient organisms carrying this might be sequenced. But I'm not sure what the question is. You obviously seem to think it's viable and your argument stands.... do you have a specific concern? – Escaped dental patient. Mar 29 '24 at 08:50
  • How do you propose to keep the DNA polymerase from building on unwound DNA strands and the PNA polymerase from building on PNA strands? Or worse, one of each trying to work on the same strand at the same time? – Cadence Mar 29 '24 at 09:49
  • @Escapeddentalpatient. My concern is that I might have missed something major that renders my idea unviable, or something that I can correct or remove. If the idea works, great! – Baron_vonCernogratz Mar 29 '24 at 10:59
  • @Cadence Answering the second part of your question first, once a polymerase has worked on a strand, another polymerase cannot touch the same strand simply because the strand is now part of a finished duplex. Polymerases need unwound single strands to work. – Baron_vonCernogratz Mar 29 '24 at 11:02
  • @Cadence To answer the first part of your question, I'd like to point you to how reverse transcriptases used by retrovirii work. The reverse transcriptase itself is a polymerase that transcribes RNA to DNA first, which the host DNA polymerase then uses to synthesize DNA which is spliced onto the genome. – Baron_vonCernogratz Mar 29 '24 at 11:06
  • The fact that no natural DNA polymerases exist that can directly read RNA, whose backbone is just 1 OH group away from DNA, implies a high degree of substrate specificity in the DNA Polymerase. Engineering a DNA/PNA Polymerase with the same level of substrate specificity therefore isn't outside the realm of possibility. – Baron_vonCernogratz Mar 29 '24 at 11:08
  • Minir point - "Melting temperature ... for a DNA-DNA duplex is 10°C"? Human body temp is what, 38 C? DNA melting depending on many things, and some micro orgs can live at very high Temps such as geysers – N Brouwer Mar 30 '24 at 01:52
  • I belive you will still have issues with discontinuous synthesis of the DNA portion of the molecule as long as you only localized unwinding of the parent molecule. "Leading" and "lag" strands are misnomer- sections of DNA lead and sections lag. See the middle part of this diagram https://en.m.wikipedia.org/wiki/DNA_replication#/media/File%3AAsymmetry_in_the_synthesis_of_leading_and_lagging_strands.svg – N Brouwer Mar 30 '24 at 01:59
  • @NBrouwer I'm sorry, I should have clarified. Leading and lagging strands in the direction of helix unwinding should be more descriptive. If you see the video I've linked above, one half of the DNA is transcribed apace of the helix unwinding (the bottom half in the video), while the other half loops around and creates a long open strand until the polymerase reaches it. I'm envisioning both halves being transcribed at the same rate as the first half. – Baron_vonCernogratz Mar 30 '24 at 05:48
  • @Baron_vonCernogratz - clarifying question - are you assuming the DNA replication begins at one end of the molecule (eg chromosome) and proceeds all the way to the other? In vivo DNA rep starts from multiple internal "origins of replication" (ori) the geometry of this is such that you always have lagging synthesis and okazaki fragments on both parental molecules. – N Brouwer Mar 30 '24 at 13:42

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Are you sure you want more stability and better error repair?

At the end of the fair evolution is caused by random mutations which are caused by instability and/or non perfect repair.

Too many mutations are detrimental for the life of the individual, but not enough mutations are detrimental for the life of the species and its genetic code.

In short: maybe DNA is the sweet spot between not having errors and having too many errors.

If nature had wanted a better solution, it would have found it.

L.Dutch
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