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RE: radon - DNA damage - yeast - input from the biologists
Friends,
Ruth is right. Going further, relevant msgs from 2 biologists are
provided below as they were sent to the biology group, re the yeast data
(even though the biologists are last to be considered in rad protection
and biophysics misperceptions of biological effects, especially
irrelevant chromosome aberrations, which can indeed be 'markers' of
radiation exposure, but are of no real significance to health effects
since the issue of producing cancer is DNA repair/mis-repair, not the
dead ends of permanently damaged chromosomes :-)
-----Original Message-----
From: RuthWeiner@AOL.COM
In a message dated 1/15/02 9:03:05 PM Mountain Standard Time,
bcradsafers@HOTMAIL.COM writes:
Do you agree that irreversible DNA damage can occur due
to ionizing
radiation exposure?
BTW: The most sensitive studies for induction of
chromosomal aberrations
(micronuclei, Cs-137) show an absolutely straight line
down to 2.3 mGy if I
recall correctly. The same seems to be true for point
mutations in somatic
cells with increasing age.
What is "irreversible" DNA damage? DNA repair also
occurs at the molecular levels.
Moreover, cell damage does not translate linearly to
organism damage, or even to organ damage. Cells die every day. Cells
are killed in a variety of ways (when I had hip surgery, plenty of
cells were killed and damaged!) That does not mean that the organism
suffers permanent damage, or that the cell damage necessarily even
propagates.
The LNT may well be an accurate representation of cell
damage. However, if the LNT were an accurate representation of
radiation damage to an organism, everyone would have some cancer, if
only because of the natural body burden of radioactivity. Moreover,
every epidemiologic study would confirm this.
Finally, cancer induction might in fact be linearly
proportional to radiation exposure, but that does not necessarily imply
a threshold. It's the threshold question we are arguing. Incidentally,
the response to CO poisoning is linear, and has a very well known
threshold.
Ruth Weiner, Ph. D.
ruthweiner@aol.com
==========================
Hi Jim;
Given the interest in the new yeast data, I though I would give some
perspective.
We did a lot of work on induced radiation resistance in yeast in the
1980's and 90's. In yeast (unlike in mammals) inducible radiation
resistance (the adaptive response) is proportional to dose and shows an
oxygen effect, a clear indication that the cells are responding to DNA
damage. We showed that the cell was responding to both DNA double strand
breaks and single strand breaks, but single strand breaks were a better
inducer. Induction peaks after a dose (in oxygen) of about 100 Gy. This
sounds huge but remember this is a much smaller genome and with much
better repair capabilities (in mammalian cells the repair induction is
at maximum after the first track of radiation goes through the cell). At
100 Gy yeast cell survival is 100%! Induction is absolutely dependent on
the presence of a functional gene Rad52. This is the gene for error-free
DNA recombinational repair (homologous recombination). This is the DNA
repair process that repairs DNA double strand breaks, as well as other
kinds of DNA damage, including DNA damage from chemical mutagens. The
other kind of recombinational dsb repair (non-homologous recombination)
is not induced and its presence or absence makes no difference to the
adaptive response. Mammalian cells use exactly the same systems. This
means that the only possible outcome of adaption is an increase in error
free repair, and therefore a reduction in the risk of mutation. This is
just what happens in rodent cells when we adapted them and reduced the
risk of transformation to malignancy from spontaneous events (i.e. the
spontaneous transformation frequency went below background) Les Redpath
just published the same result using human cells. We have recently shown
that low doses can reduce spontaneous transformation in cancer prone
mice(unpublished). Pre-treatment of yeast with adapting doses of
radiation can prevent mutation from subsequent exposure to potent
chemical mutagens. Chemical mutagen exposure can also induce radiation
resistance. We showed the same thing happens in human cells after
exposure to the chemotherapeutic agent cisplatin.
It looks very much like (with a very few exceptions) what happens in
yeast is an excellent predictor for mammals.
This adaptive response to radiation in yeast is part of a larger stress
response. Exposure to many things can induce the same response. We also
sent a lot of time looking at the reciprocal induction of heat and
radiation resistance by exposure to heat or radiation. Heat stress
induces radiation resistance by exactly the same process as radiation
exposure.
Most of this and more is published. Just search PubMed under my name.
Ron Mitchel
================
At 6:55 PM 02.1.16, +0900; Sohei Kondo wrote:
The perspective informations given in the mail of January 15 by Ron
Mitchel
in regard to the inducible radiation resistance due to
radiation-enhancement of HR (homologous recombination repair pathway),
are
very interesting.
It should, however, be noted about the difference between yeast and
mammals in regard to radiation resistance repair as follows.
In mammalian cells, HR is not inducible by radiation although the
mammalian HR pathway is governed by Rad51, Rad52 etc genes as the case
of
yeast. Furthermore, Rad51(-/-) cells are viable in yeast but not viable
in
mice (Lim and Hasty: Mol Cell Biol 16, 7133, 1996) probably the size of
the
genome in mammalian cells is too large to tolerate DSBs (double strand
breaks) spontaneously occurring. About ten DSBs per cell cycle occur
spontaneously in human cells. Rad51 protein is indispensable for
mammalian
cell growth. Yet, after Rad51 protein is synthesized in S to G2 phase,
it
is destined to be degraded after M phase; Rad51 protein is resynthesized
in every cell cycle (Yamamoto et al. Mol. Gen. Genetics 251. 1-12, 1996)
.
Therefore, the mechanism of radiation resistance via HR is totally
different between yeast and mammals.
Sohei Kondo
========================
Friends;
Sohei Kondo describes some interesting differences between yeast and
mammalian cells, and the regulation of genes involved in homologous
recombination in mammalian cells. He concludes that HR is not inducible
in mammalian cells. There is an alternative viewpoint.
At low doses in mammalian cells, the classic test of the adaptive
response is the micronucleus assay. Mammalian (including human) cells
adapted by exposure to low doses at low dose rates have an increased
capacity to repair micronuclei introduced by a second large dose, and
they also repair those micronuclei at a faster rate. Micronuclei are
pieces of broken chromosomes and therefore are the result of DNA double
strand breaks. Low doses therefore increase the ability of mammalian
cells, including human cells, to repair DNA double strand breaks at a
faster rate than unexposed cells. This increased repair capacity is
error free, since it reduces the spontaneous rate of transformation to
malignancy to levels below the normal spontaneous rate in both rodent
and human cells, and protects mice against both radiation induced and
spontaneous cancer. We have, therefore, a DNA repair system that is
inducible by low doses, and repairs DNA double strand breaks in an error
free manner. All these properties are the same as those seen in yeast.
And just as in yeast, this increased double strand break repair capacity
in human cells can also be induced by other DNA damaging agents, so it
is responding to the same kind of cellular signalling process. The only
DNA repair system known that has these properties is homologous
recombination. While this is not proof that HR is the DNA repair system
in man that responds to low doses, any alternative hypothesis seems less
likely, particularly since these adaptive responses appear to be
evolutionarily conserved all the way from bacteria up to man.
Ron Mitchel
=====================
Regards, Jim Muckerheide