From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Tue Apr 22 2003 - 09:20:40 MDT
On Tue, 22 Apr 2003, Rafal Smigrodzki, commenting on Damien's
comments wrote:
> nuclear genes, usually present in only two copies, achieve large protein
> output is by having relatively stable mRNA's which act as amplifiers of
> their function.
This may be true -- though I'd like to see some data on what
regulates the mRNA degradation in eukaryotes. I'm reasonably
certain that in bacteria (prokaryote) mRNAs are recycled fairly
rapidly so they can change state more quickly than eukaryotes.
> If you transfer the mtDNA to the nucleus and set the
> nuclear-encoded mtRNA polycistronic transcript to a high copy number (by
> stabilizing it in the cytoplasm), you should be able to make the same amount
> of protein as made from the 10,000 mtDNAs currently present in our cells.
Here I'm not so sure -- any context I've seen polycistronic mRNAs
discussed it is always in prokaryotes. I don't think I've ever
encountered polycistronic eukaryotic mRNAs. But one can get the
same effect with multiple gene copies as is the case with the
ribosomal (rDNA) or transfer (tDNA) genes (which produce (rRNA & tRNA).
That is common in the larger eukaryotic genomes.
Polycistronic for those who don't know means that RNA polymerase
transcribes a single messenger RNA (mRNA) with multiple genes on
the same RNA strand. It is useful for sets of genes one wants
to operate in conjunction with each other.
> I don't know if there is an increase in the mutation rate at highly
> transcriptionally active loci (where the sense DNA strand indeed has to be
> pulled open for the RNA to be synthesized), but this couldn't be a higher
> mutation rate than what you have in the mtDNA now, with all mitos actually
> recycling their DNA about every two weeks
At normal body temperatures, if you have two single-strand breaks on
opposing strands (due to intermediate stages of DNA repair processes
derived from various types of DNA damage) in a DNA strand at separations
from 8 to 18 base pairs (depending on the GC:AT composition) then the
DNA will "melt" producing a double strand break. At fever temperatures
the separation distance increases slightly. During transcription
I believe RNA polymerase effectively melts DNA over a larger distance
still (dozens of base pairs?) so one could get a double strand break
from single strand breaks located at even larger distances.
So I would say that yes -- highly transcriptionally active loci would
be more likely to accumulate mutations since they are more likely
to incur double strand breaks which produce sequence corruptions
if they are repaired by the non-homologus end-joining (NHEJ) DNA
repair pathway.
[Side note -- this conversation has been quite useful with respect
to my ideas on a "Grand Unified Theory of Aging".]
I agree with Rafal that the nuclear mutation rates should be lower
than the mitochondrial mutation rates. I would expect there ought
to be data in PubMed on this.
Robert
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