Does expression increase the genes chance of mutation?
dellaire at odyssee.net
Sun Jul 13 22:15:21 EST 1997
Mike wrote previously,
>From: Mike Lamb <mikejonlamb at earthlink.net>
>To: bionet-genome-gene-structure at net.bio.net
>Subject: Q: Does expression increase the genes chance of mutation?
>Date: Sunday, July 13, 1997 7:05 PM
>I would like to know if a gene is more susceptible to chemical
>carcinogens as the gene is being expressed. In other words, do mutations
>occur more often in expressed genes?
When a gene is transcribed this can correlate with hypersensitive regions
within or nearbye the gene (coinciding presumably with the destabilization
of nucleosome/DNA contacts at promoters or enhancers for example). The DNA
is more accessibile to Dnase I or micrococcle nuclease and this results in
the characteristic Dnase hypersensitivity profile when genomic DNA is
digested followed by Southern analysis. As well, DNA damage by ionizing
radiation is affected by chromatin structure and removal of histones can
increase the radiation sensitivity of DNA. So my guess would be that for
some carcinogens a transcribed gene is perhaps a very good target for
damage. Unfortunately... or fortunately for us, transcribed DNA is also
the first to be repaired as members of the basal transcription apparatus
(ex. TFII D) also function in DNA repair.
So Yes I would expect transcribed DNA would be more accessible to certain
classes of carcinogens (clastogens or those that produce free radicals,
i.e. that damage chromosome directly rather than carcinogens that modulate
signal transduction as a means of transforming cells such as phorbol
esters, indole alkaloids and poly acetates (all which act through protein
kinase C pathway)).
But if you are worrying about increase of mutations in transcribed DNA (or
active genes) you are fighting the increased repair in these genes as well
as negative selection for "major" disruptions of genes vital to the cell
(i.e. the cell just dies).
In fact inactivity can be a bigger driver of evolution and genomic
change... case in point is the neoteny of salamanders in which the little
critters increase the amount of "junk" or repetitive DNA during this time
in regions that are not transcribed until adult hood (which they never
reach because of their neotenic state). The length of time the salamander
population has been in a neotenic state can be measured from the amount of
repetitive DNA accumulated. A sort of junk DNA clock.
(see: Martin and Gordon (1995) Differentiation trees, a junk DNA molecular
clock, and the evolution of neoteny in salamanders. J. evol. Biol (8)....
don't know the page as I have only the galley proof)
For a review on carcinogens and the spectrum of damage with repect to the
International Commission for Protection Against Environmental
Mutagens and Carcinogens. Working paper no. 5. Impact of the molecular
spectrum of mutational lesions on estimates of germinal gene-mutation
Mutat Res 1994 Jan;304(1):119-137
Hope this helps,
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