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Perichromosomal Particles and their Role in Cellular Aging (Hypothesis)
Posted on: May 4, 2005

According to the proposed hypothesis, the memory of a cell about the achieved state of cytodifferentiation is based on the existence of a postulated genetic structure termed here as a "printomere". A printomere is a relatively small linear DNA fragment that is laterally located on the chromosomal body and armed at its termini with peculiar analogs of chromosomal telomeres, which in this case are designated as "acromeres". The printomere locates along its chromosomal original "protoprintomere" and is bound to this chromosomal segment via proteins. The printomere codes for socalled fountain RNAs (fRNAs). Molecules of fRNAs as a part of ribonucleoproteins, or fRNPs, specifically bind to the complementary for them DNA sites, or "fions", that are dispersed nearby many structural genes. fRNP-fion complexes help to open, for a very short time, closed ion channels in the inner nuclear membrane, and this occurs strictly nearby corresponding genes.
Dosed and local entry of the specific ions from the perinuclear cistern of the nucleus modifies the local pattern of the chromatin decompaction and modulates the expression level of the corresponding genes. The implied role of the fRNAs was considered in the so-called "fountain theory".
Transcripts (fRNAs) coded by printomeres participate in the creation and maintenance of the specific patterns of decompaction and compaction of chromatin, which are characteristic for corresponding cytodifferentiations. Printomeres of various differentiations differ in their nucleotide sequences. The printomere and its chromosomal original, the protoprintomere, located co-linearly, side by side with it, have their own ori. Their length may vary from several thousands of base pairs to tens of thousands of b.p. Printomere bound by its arms to the chromosomal DNA with chromatin proteins is able to pass over the replicative forks during printomere replication and replication of the chromosome. That is why any printomere can be stably retained on the chromosomal body in the course of numerous cell divisions. Owing to printomeres, cellular memory about the proper structure of chromatin decompactions is created, kept, and can be carried through the succession of doublings of differentiated cells.

The Printomere under the Microscope?

If the printomere exists as an autonomous unit in a complex with chromatin proteins, then, by analogy to the "ultramicrochromosome", it could be termed as the "printosome", and as such, it could be identified by using some pertinent techniques. Whereas the methods of molecular biology in their application to printomeres is a task of the possible future, some observations of cytologists on chromosome morphology compel me to suppose that some structure-a candidate for the role of printosome-has already been revealed. Uruguayan researchers, visualizing results of T-banding, have discovered tiny cavities in chromosomes at the spots of some removed chromatin fraction. These unusual cavities were found in paracentromeric regions, i.e., in regions on both sides of the centromere and in subtelomeric regions. Printomeres could reside just in these regions, since these segments are most conservative and resistant to recombination; and the conservatism of printomeres is favorable for preserving of species-specific properties. The intrachromosomal cavities, from which the printosomes could be potentially extracted, were found in identical places of members of one and the same chromosomal pair; the cavities occurred to be totally free from chromatin. When, on the background of the preserved continuity of DNA, printomeres are removed from the chromosome, the protoprintomeres as chromosomal originals of printomeres should, of course, keep residing in chromosomes, being a part of the continuous chromosomal DNA.

On the Role of Printomeres in Cellular Aging

The nucleus enlarges during cell senescence, possibly due to attempts of homeostatic systems of the cell to increase to the maximum the number of elements that are unpacked and recruited into the operation of the fountain system, in order to intensify as much as possible the expression of genes under conditions of a deficit of fRNAs coded by shortened printomeres. The truncation of printomeres, due to DNA end under replication and DNA end under repair synthesis of linear printomere molecules, could lead to a gradual, rather than drastic, decrease of gene productiveness in a differentiated cell. The smoothness of this process, as far as it depends on printomere's shortening, is determined by the following circumstance. Providing the printomere contains several repeats which code for fRNAs, the loss of each in succession of them reduces the productivity of the printomere due to the decrease in its "gene dose". Shortened by one or more repeats, the printomere is still able to be transcribed and to remain resistant to nucleases.
This is possible provided that the spacers located between the printomere's repeats are identical to acromeres in their sequence and if they are able to take the acromere's function of a cap, when any inner spacer appears at the absolute end of the printomere.
The acromere is a sequence containing a series of short repeats. Acromeres are localized at both termini of the linear double-stranded DNA of the printomere. Together with covering proteins, each acromere protects its printomere from nucleases and, in addition, it plays a role of a buffer that, like telomeric DNA, is shortening because of the DNA end underreplication and the DNA end under repair. Acromeric buffer, sacrificing itself, preserves the safety of those informatively significant printomere sequences in which fRNAs specific for a given cytodifferentiation are encoded. The definition "acromere" is chosen for these telomere-like structures of the printomere in order to avoid confusion with the true chromosomal telomeres. Besides acromeres and a single ori, each printomere has, as it was already stated, sequences coding for fRNAs. These coding sequences are represented in the printomere by a series of repeats separated by the above-mentioned spacers whose sequence may be similar or identical to the sequence of acromeres. In such a case, the loss of an acromere and of the terminal informational repeat coding for the fRNA will not immediately lead to complete loss of the activity of the printomere, since the interior repeats of the truncated printomere still can retain their transcriptional activity. Nonetheless, the "gene dose" of the shrinking printomere persists gradually decreasing. This inevitably leads to decline in the concentrations of the corresponding fRNAs that, in turn, should decrease the portion of the adequately decompacted chromatin and reduce the activity of transcribing genes. In this way, shortening of the printomere must inevitably weaken the activity of a cell and reduce its homeostatic potential. That is why the shortening of printomeres appears to be the primary cause of cellular senescence.

Source: Olovnikov A. M.; Notes on a "Printomere" Mechanism of Cellular Memory and Ion Regulation of Chromatin Configurations; Biochemistry (Moscow), Vol. 64, No. 12, 1999, pp. 1427-1435. Translated from Biokhimiya, Vol. 64, No. 12, 1999, pp. 1689-1698 (1999).
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