Background
DNA replicates itself. That is Biology 101. The process is quite complex and
any biology student required to rattle off the procedure on an exam can confirm.
Although there are separate kinds of topoisomerase,
1 they
perform the same essential function within the process of replication.
What is topoisomerase?
In each human cell, there are approximately 2 meters of DNA compacted within
a nucleus of the diameter of about 10 micrometers.
2
For perspective, imagine that the nucleus is represented by a standard basketball.
The length of all the DNA compacted into the ball would go round-trip between the
earth and the moon just shy of twice. Topoisomerase has the job of ensuring that
the shape of DNA is manageable. Add in the fact that DNA is not just a helix, but
a double-helix. As one might imagine, the task of trying to do anything productive
with this material presents very serious concerns that need to be dealt with. During
replication, the topology (i.e. the shape and structure) of DNA and the movement
in unzipping result in issues like tangling and kinking, so the process faces a
formidable and complex challenge of bioengineering.
3
It’s topoisomerase’s job to alleviate those issues so they don’t halt the replication
process.
4 If DNA cannot replicate,
then an organism cannot grow. Additionally, DNA doesn’t just unzip for replication.
It unzips in a process called transcription, which, with the help of RNA, is the
first half of producing vital proteins in the cell.
Two examples might help illustrate some of the mechanical concerns that arise.
Without even trying, the ordinary use of a wired phone produces coiling in the helical
cord. No extraordinary spinning or energy is required to produce the effect, but
it doesn’t take long for the cable to go from fresh and neat to knotted spaghetti,
which seem to never come out. Even if the tangle is gone, there always seems to
be a small bend or a missing turn were the tangle was. The second illustration may
serve to demonstrate the problem of kinking just prior to cutting the DNA strand
in two. To demonstrate the concept, you can take a piece of twine and try to unwind
it by pulling away both its twisted strands away from each other. A "Y"-shape forms:
the two strands being pulled apart are each the top segments of the "Y" and the
rest of the twine is the bottom. Now at some point, enough tension will build up
at the center of the "Y" to where you can no longer pull the strands apart. Fortunately,
topoisomerase is there to work out these sorts of problems. Its process is so vital
and complex that some have referred to topoisomerase as the "magicians of the DNA
world"
5 because of their uncanny
ability to manipulate the DNA strand and master its topology.
The Problems for evolution
1: Does not fit early evolutionary models for an ancestral topoisomerase
It is still unclear how exactly topoisomerase originated on an evolutionary model,
particularly because all the different types of topoisomerase appear to have originated
independently of one another.
6
A core tenet of evolutionary biology is that all life can be traced to a common
ancestor (more technically, LUCA: last universal common ancestor). It is natural
to assume that LUCA would have some master topoisomerase that would have developed
into the varying domains
7 of
natural life: Achaea, Bacteria, and Eukaryota. But, this seems to be an incorrect
inference that does not align with the actual data.
8
It is speculated that topoisomerase might have emerged with either an ancient
viral lineage or a LUCA that began with RNA genetic information or a combination
of the two.
9
These RNA-infused
models would be controversial, because such scenarios involve the already contested
10
(among researchers in that field) RNA-world hypothesis for the origin of life. And,
the progressive introduction of topoisomerase and other necessary replication proteins
into the evolutionary lineup seems an inventive proposition, but requires massive
amounts of biological informational leaps that are unfounded, especially within
the limited time window for the emergence of life on earth that evolution demands.
2: Conceptual Paradox11
Most of all, the origin of topoisomerase presents a chick-and-egg paradox. To
replicate itself the DNA molecule needs topoisomerase to unwind it. And, DNA would
need to code for a protein to do the unwinding (in order to pass on the genes to
code for topoisomerase). It’s like having a car with no gas. You need to drive to
the gas station to get gas, but you need gas to get to the gas station. DNA might
have obtained topoisomerase from somewhere else, but the instant it makes a copy
of itself, the other strand needs topoisomerase also. The scenario requires the
leap to the reality, where DNA actually codes for this protein itself. That is not
to mention that the actual mechanics of unwinding get even more complicated, because
topoisomerase is able to cut and re-join small sections of DNA, which require precise
biochemistry to ensure the right pieces get linked back up with each other and at
the proper speed. Too slow, and the DNA doesn’t unwind fast enough for cell division
(mitosis) and the cell dies before replication can occur.
12
Too quickly, and the cell can set off its own self-destruct sequence (apoptosis)
or cause irreversible damage to the genes that results in cancer.
13
Conclusion
Lastly, it is also important to keep in mind that this is only a piece of a wider
issue for evolutionary biology to explain DNA replication in general: proteins that
function as stabilizing clamps, ones that actually unzip the DNA strand, others
that error-check the new copies, or the fact that one side of the DNA is duplicated
backwards and in sections…
References
2. Joseph E. Deweese and Neil Osheroff,
"The DNA cleavage reaction of topoisomerase II: wolf in sheep’s clothing,"
Nucleic Acids Research 37, No. 3 (2009): 738-748.
3. Ibid.
4. James J. Champoux, "DNA topoisomerases: structure, function, and
mechanism,"
Annu Rev Biochem 70 (2001): 369–413.
5. James C. Wang, "Cellular roles
of DNA topoisomerases: a molecular perspective,"
Nature Reviews Molecular
Cell Biology 3 (June 2002): 430-440. Wang also makes use of this phrasing
in his conclusion of his ‘Minireview’ in "Topoisomerases: Why So Many?"
in
The Journal of Biological Chemistry vol. 286, 11 (April 1991):
6659-6662.
6. Patrick Forterre and Daniele Gadelle,
"Phylogenomics of DNA topoisomerases: their originand putative roles in
the emergence of modern organisms,"
Nucleic Acids Research (2009),
1. The two coauthored a similar article with Simoneta Gribaldo and Marie-Claude
Serre, called "Origin and evolution of DNA topoisomerases," in
Biochimie
(April 2007): 426-446.
7. A
domain is the largest
formal classification of living organisms on earth. By contrast, a
species
is the smallest formal classification.
8. Forterre and Gadelle, 1, 12 (and
throughout the article in fact).
9. Ibid.
10. Patrick Forterre, one of the
authors mentioned in this article, notes the RNA-world hypothesis, but references
its implausibility on page 146 in the chapter entitled
Origin and Evolution
of DNA and DNA Replication Machineries of "The Genetic Code and the
Origin of Life," published by Kluwer Academic and Plenum Publishers. Jonathan
Filée and Hanny Myllykallio.
11. This paradox seems lost on
some. The article by Allyn J. Schoeffler and James M. Berger entitled, "DNA
topoisomerases: harnessing and constraining energy to govern chromosome
topology,"
Quarterly Reviews of Biophysics 41, 1 (2008): 41–101,
puts forth: "Understanding topoisomerase specialization is necessary to
illuminate the evolutionary interplay between supercoiling homeostasis and
the requirement for multiple topoisomerase activities to shepherd DNA through
transcriptional, replication, and recombinational processes." The authors
acknowledge that topoisomerase is subject to the mechanisms of evolution.
How exactly does a mechanism necessary for evolution to work – even at the
basic level – get thrown into the mix if it’s not functional with the first
strand of DNA? That is not to say that it cannot improve or adapt with time,
but it must work from the onset to begin with. And not just it, but DNA
and its other requisite enzymes and processes.
12. Deweese and Osheroff, 741-742.
13. On the other hand, however,
the essential nature of topoisomerase to cell replication (which requires
DNA replication) has been exploited in anti-cancer drugs, which target the
topoisomerases within the unwanted cells.
Image entitled "Replication complex" by Boumphreyfr - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.