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DNA damage and repair [was RE: fountain of youth]

Robert Bradbury rbradbur at hardy.u.washington.edu
Thu May 7 09:28:58 EST 1992


The first copy of this did not appear to reach USENET, apologies to BIONET
people who have seen it already.

In article <1992Apr24.135729.17184 at yang.earlham.edu> allens at yang.earlham.edu (Allen Smith) writes:

>In article <9204201824.AA19658 at rust.zso.dec.com>, french at RUST.ZSO.DEC.COM
> writes:
>>
>> I would expect eggs to self-destruct (and spontaneous abortions) to
>> occur at a much higher rate than they actually do unless an error
>> correction mechanism was also at work that corrected DNA errors
>> when fertilization occurs.

Yes!  See: Generoso et al in "Genetic Lesions Induced by Chemicals in
Spermatozoa and Spermatids of Mice Are Repaired in the Egg.", PNAS 75:435
which seems to indicate that fertilized egg division does not occur
until DNA repair activity is complete.  The sperm have alot of vitamin
C to protect them from oxidative damage and then any they do have gets
repaired.

>>
>        I suspect that DNA damage is indeed involved in aging- but the
>mechanisms that prevent it are one of the things that turn off in old age.
>If someone has some data on DNA repair efficiency as related to aging,
>that would be nice.

Warner and Price in J. of Gerontology, 1989, 44:45-54 cite a 1985
review by Tice and Setlow, concluding there is no consensus on
the relationship between age and DNA repair capacity either in vitro
or in vivo for cells from rats, hamsters and humans using UV-induced
unscheduled DNA synthsis as the assay for DNA repair.  Experiments
involving carcinogenic agents which produce alkylated bases and
bulky adducts showed either decreases in DNA repair capacity or
no change.

However, one might then ask why does Bruce Ames finds an increase in
the number of damaged DNA bases?  I would point to studies such as
Semsei et al, 1989 which find a decrease in mRNA levels and the enzyme
activities of CuZn superoxide dismutase and catalase in rats.
So, the conclusion is not that our repair capacity suffers a great
hit but that as we age the rate of damage is increased beyond our ability
to repair it.  It is worth noting that while the times to repair DNA lesions
within transcribed genes are similar in rats and humans, the rats take much
longer to repair damage in non-transcribed (currently inactive) genes.

> Given that much DNA damage takes place at the time of replication,
>it's unsurprising that egg cells wouldn't have that much damage.

Iffy statement, one of the reasons replication pauses after S phase
(in G2) is to repair any damage that may be present.  I would argue
that egg cells do not have much damage because they have few active
genes (leading to the DNA being protected by the histones) and their
low energy requirements reduce oxidative damage to cellular components,
particularly DNA.

Robert Bradbury					uunet!sftwks!bradbury




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