feedback requested on ideas(modified)

Iuval clejan clejan at mindspring.com
Sun Feb 25 08:46:46 EST 2001


> > Hang on.  This list covers only the simple case of mutations that
cause
> > modulation of expression of the same protein, in the same cell, that

> > the mutation is in the gene of.

> Not at all. All except possibly (2) are about mutations for genes
other
> than the ones for the
> protein being modulated.

> > 4 and 5 also count, don't they?

I was thinking of (4) (a mutation of  rDNA) as affecting translation of
any other mRNA, and (5) (a mutation of mtDNA) affecting all cellular
processes requiring ATP (and from your latest info, (5) also influences
many cellular processes through modulation of oxidative stress). If
mitochondria can divide in quiescent cells and there is a selective
advantage to the defective ones, then (5) is still a good example of a
mutation which has a continuous effect on production of all proteins.

>> proteins will still work, at variably reduced efficacy, when they
have
>> suffered point mutations.  There are of course awfully many possible
>> mutations in each gene, and in virtually any gene there will be a
range
>> of reductions in function right the way from tiny to complete loss of

>> function, depending on which base pair is changed and to what.
>> Thus when you consider expression of a protein, this can be affected
by such
>> mutations not only in ribosomal components but in all the other
processes
>> relevant to protein synthesis -- tRNA synthesis/acylation,
transcription,
>> mRNA splicing, mRNA export from the nucleus, etc -- and also, of
course,
>> in mutations in any of the upstream transcription factors that
regulate
>> the expression of the protein, or in the factors that regulate those
>> factors' expression, and so on.  When you consider that enzymes may
or
>> may not be up-regulated in expression to compensate for mutations
that
>> somewhat diminish their efficiency, the complications become even
bigger.

I understand that this can happen. My question is: is it causative in
aging? If we look at a particular protein important for the
function of a particular cell type and compare young vs old cells:
(1) does the mRNA cease to be processed
(transcribed/spliced/transported/translated), or is processed at a lower
rate (need to answer this on a cell by cell basis, not average over
population of cells)?
(2) does the DNA and or mRNA and/or protein  accumulate increasing
errors and if so does the protein suffer increasing lack of function?

It may be that (2) is answered affirmatively but that only (1) is
relevant to aging. We can use lots of old cells and lots of young cells
and may find for example that (2) happens for the young or old cells
when treated as separate populations as well as between the two
populations, whereas (1) only happens between old and young cells.
Perhaps (2) is only relevant to aging when it happens to repair enzyme
coding genes, which affects one of the 6 mechanisms (in the original
post) which in turn produces (1)

> As far as I know nobody has looked at time averaged mRNA expression.
> What is the time scale for which genes (coding for proteins that are
> involved in decreased organ function with age and associated proteins,

> not for genes associated with daily metabolic changes) are
> transcriptionally active, all else being equal?

>> Do you mean, how fast does mRNA expression oscillate?  I've no idea,
but
>> it's certain to be very different for different proteins.  But you
don't
>> need to look on purpose for time-averaged expression, because in
general
>> cells will not oscillate synchronously (except for genes regulated by

>> daylight, for example).  So the average of a lot of cells suffices.

But then you don't know if you're averaging effectively over time
(because they're fluctuating asynchronously and at any one time you get
from the population of cells a representation of the time dependence for
each cell) or over a (possibly binary) distribution of cells, for which
there is no time variation. Ideally, we should find a protein which
doesn't fluctuate over small time scales, or more precisely for which
the magnitude of small time fluctuations is small compared with the
magnitude of large time fluctuations.

> What regulates their division?

>> No one knows; the model in my BioEssays paper is a possibility.

I will look it up.

-Iuval








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