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A Theory of Marginotomy
The Incomplete Copying of Template Margin in
Enzymic Synthesis of Polym&otides and
Biological Significance of the Phenomenon?
A. M. OLOVNIKOV
1. The Problem
This paper considers some aspects of the mechanism of DNA replication
near the ends of polynucleotide chains which may be of considerable
t Preliminary accounts of this work have been published in Dokl. Akad. Nauk SSSR
(1971),201, 1496and reportedat the 9th International Congress of Gerontology in Kiev,
July 2-7 (1972),3,42.
181
182 A. M. OLOVNIKOV
biological interest. I suggest that a special phenomenon exists near the ends
of DNA helix during replication, such that it is not possible for a poly-
nucleotide chain to be completely copied under certain conditions. This
phenomenon, which was not considered in the classical model of DNA
replication (Watson & Crick, 1953) has been called marginotomy (Olovnikov,
1971).
The principle of marginotomy. Marginotomy is the formation of replicas
shortened relative to the template. There are two possible mechanisms of
formation of shortened replicas : the first being “polymerase-dependent”
marginotomy and second “RNA-primer-dependent” marginotomy. Poly-
merase-dependent marginotomy results from the existence of a postulated
catalytically inactive zone (“dead zone”) in the DNA-polymerase molecule.
This zone lies between the catalytic centre of the polymerase, which catalyses
incorporation of successive residues of deoxyribonucleoside-S-3 phosphates
into growing replica, and an edge of the enzyme molecule. This edge is in
contact with the template nucleotide which is furthest from the catalytic
centre. That terminal part of the template, which is equal in length to the
“dead zone” of DNA-polymerase (in Fig. 1, one can see two such zones),
will not be reproduced in the replica. The replica will therefore appear
incomplete, shorter than the template by a length equal to the above-
mentioned inactive zone. Hence, some terminal nucleotides of the template
will remain uncopied in the course of DNA doubling. The second mechanism
of marginotomy is due to the requirements of some DNA-polymerases for
some RNA-primer to initiate DNA replication. This primer must be removed
from the final product and thus the DNA replica will be shortened by the
length of RNA-primer.
ho. 2. The scheme of proximal polymemse& pendent marginotomy of DNA. al, The
molecule of a sin&segment DNA-polymerase with a “right-edge” position of the cata-
lytic centre.
above have two identical catalytic centres per molecule. Thus they are
“bis-catalytical” tandems.
(7) Another type of tandem, “a bis-translocational” tandem, is also
possible. In this case, the catalytic centre is localized between two indepen-
dently acting translocational segments each of which is capable of producing
the movement of the entire tandem, even if the second translocational
segment protrudes beyond the template’s end and is “paralyzed”. The centre
for recognition of the initiating sites of the template is located only in the
front segment of such a bis-translocational tandem. In this case, the single
catalytic centre can copy both ends of the template but only if the growing
double helix is not an obstacle to the expression of translocational activity
of the rear segment during replication of the 5’ terminus of the template.
(8) Mono-block DNA-polymerase functions in the majority of somatic
cells, namely those which possess limited cell doubling potential. Each
linear chromosome in a normal cell of an eukaryote containing a mono-block
DNA-polymerase is subject to marginotomy, unless the chromosome
possesses circular replicons at its ends. Marginotomy leads to edge deletions
in the end-genes of chromosome. As a means of temporary protection of
vital genetic material in the telomere against the destructive effect of mar-
ginotomy, each chromosome possesses two specialized genes, the so-called
end-genes or telogenes (Muller, 1940), located at the opposite ends of the
DNA mononeme. It is assumed that telogenes bear no genetic information,
but fulfill “buffer” function. In the course of each mitosis, the telogene is
marginotomically shortened by the RNA-primer length and/or by an
appropriate length I,,, (see Figs 1, 2, 3) thus protecting informative genes
from marginotomy. A telogene also has the function of a starting point of
the end-replicon of a chromosome. A telogene consists of a series of starting
sites (or a series of “recognons”); the polymerase starts each time from the
3’-terminal starting site, i.e. from the 3’-recognon. This recognon will not
be reproduced from the 5’- or/and 3’-end of a DNA strand in the daughter
double helix because of marginotomy. After disappearance of the last
recognon of a telogene, the whole end-replicon of telomers in a daughter
mononeme of DNA will not be replicated.
(9) Genes within the end-replicons in chromosomes which neighbour the
last recognon of a telogene, are vital for maintaining various structures and
functions of a cell. Most important among these are genes specifying RNA-
polymerase or other parts of the transcriptional machinery. Disappearance
of end-replicons in chromosomes and, hence, disappearance of the above-
mentioned genes should lead to pathological changes in different cellular
structures and functions, including changes in karyotype, to cell ageing, and
later to death of the cells.
MARGINOTOMY THEORY OF AGEING 187
(10) Marginotomic death of some dividing cells of eukaryotes, including
clones participating in regulation of the hormonal status of the body (death
of cells participating in regulation of the activity of hypothalamus and of
others homeostatic centres), is the primary cause of ageing in multicellular
organism.
(11) Tandem-DNA-polymerases are present in cells capable of unlimited
division, for example, in tumor cells, in permanent cell lines, in stem cells,
in germ cells, and in some other cases.
4. Prediction
It seems quite expedient to search for cellular factors controlling the
mechanisms of marginotomy and antimarginotomy in template synthesis of
polynucleotides, which might repress or derepress, correspondingly, genes
determining monosegment DNA-polymerase and tandem-DNA-polymerase
or other means of antimarginotomy. Such factors (“marginotomites” and
“antimarginotomites”) would, probably, regulate the duration of life of
different cell clones and of the organisms which are composed of them.
It seems also quite important to identify the genes of end-replicons of
chromosomes. Possibly among them will be found the genes involved in
transcriptional machinery. Transduction into chromosomes of additional
doses of such genes as well as artificial lengthening of the telogenes could be
a means of delaying ageing of proliferating cell clones.
Thus, the terminus is the heel of Achilles of the DNA double helix, but
it can be protected by antimarginotomy.
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