RESUMEN

We found that some morphological properties of the pineal gland and submandibular salivary gland of mice are significantly distinct at the new and full moon. We suppose that the differences are initiated by the displacements of the electron-dense concretions in the secretory vesicles of pinealocytes. This presumably occurs under the influence of the gravitational field, which periodically changes during different phases of the moon. It seems that the pinealocyte is both an endocrine and gravisensory cell. A periodic secretion of the pineal gland probably stimulates, in a lunaphasic mode, the neuroendocrine system that, in turn, periodically exerts influence on different organs of the body. The observed effect probably serves, within the lifelong clock of a brain, to control development and aging in time.

Asunto(s)

RESUMEN

The non-coding and repetitive sequences constitute a great amount of higher eukaryotes genomes, but the elucidation of its role and mechanisms of action is now at the very beginning. Here we found, that internal telomeric repeats in Danio rerio are colocalized with some repetitive elements, namely, hAT and EnSpm repeats, which are highly represented in vertebrate genome. While investigating one of genome regions, containing two pairs of such repeats in close proximity we found, that it is transcribed. RNA-dependent structures, containing this sequence, were revealed in D. rerio fibroblast nuclei, which may serve as evidence of functional relevance of repetitive elements in genomes or of their transcripts.

Asunto(s)

RESUMEN

An explanation of the role of primordial germ cell (PGC) migration during embryogenesis is proposed. According to the hypothesis, various PGCs during their migrations through an early embryo are contacting with anlagen of organs and acquiring nonidentical organ specificities. An individual PGC gets such an organ specificity, which corresponds to specificity of the first anlage with which this PGC has the first contact. As a result, the cellular descendants of PGCs (oocytes or spermatocytes) will express nonidentical organ-specific receptors, hence becoming functionally heterogeneous. Therefore, each clone of germ cells becomes capable of recognizing specifically the molecular signals that correspond only to "its" organ of the body. Such signals are produced by the body's organ when it functions in an extreme mode. Signals from the "exercising" organ of the body are delivered to the gonad only via the brain retransmitter, which is composed of neurons grouped as virtual organs of a homunculus. Homunculi are so-called somatotopic maps of the skeletomotor and other parts of the body represented in the brain. Signals, as complexes of regulatory RNAs and proteins, are transported from the "exercising" organ of the body to the corresponding virtual organ of the homunculus where they are processed and then forwarded to the gonad. The organ-specific signal will be selectively recognized by certain gametocytes according to their organ specificity, and then it will initiate the directed epimutation in the gametocyte genome. The nonrandomness of the gene order in chromosomes, that is the synteny and genetic map, is controlled by the so-called creatron that consolidates the soma and germline into a united system, providing the possibility of evolutionary responses of an organism to environmental influences.

Asunto(s)

RESUMEN

An suggestion is put forward according to which the incomplete restoration of membranes in irradiated brain cells can self-perpetuate, down regulate their activity and accelerate ageing.

Asunto(s)

RESUMEN

A hypothetical mechanism for rapid and nonrandom emergence of evolutionary adaptations is proposed. It is supposed that some transcription factors and transcription regulators that are able to cross membranes can leave the cells of their origin and move within the organism using a specialized transport system when individual development occurs under conditions extreme for the given species. This system, in particular, connects soma with germline. The supply of germline cells with unusual transcription regulators changes the balance of their nuclear regulatory RNAs, thus initiating RNA-dependent epigenetic modifications of the germline genome and therefore changes in phenotypes of the progeny. It is highly probable that some of these phenotypes are adaptive and lay the basis for the origin of the next biological species. The proposed mechanism can serve as a basis for a new theory of the origin of species.

Asunto(s)

RESUMEN

As the basis for the lifelong clock and as a primary cause of aging, a process of shortening of hypothetical perichromosomal DNA structures termed chronomeres is proposed in the CNS. The lifelong clock is regulated by the shortening of chronomere DNA in postmitotic neurons of the hypothalamus. Shortening of these DNA sequences occurs in humans on a monthly basis through a lunasensory system and is controlled by release of growth hormone discharged from the anterior pituitary directly into the hypothalamus via local blood vessels. In adults, this process is under control of the pineal gland. It is further proposed that different forms of Alzheimer's disease (AD) are caused by somatic and inherited deletions of chronomeres followed by a further abnormally accelerated decrease in their activity, resulting in failures of neurotrophic and neuroendocrinal activities and in various cellular imbalances. In this model, AD is considered as a segmental progeria caused by shortening of anomalous chronomeres that are partially deleted in early development. It is proposed that a calorie-restricted diet retards chronomere shortening due to a local deficit of growth hormone in the surroundings of hypothalamic cells, thus slowing the lifelong clock and delaying aging. Calorie restriction increases lifespan by preserving mitochondrial and other organismal functions owing to the decreased chronomere shortening.

Asunto(s)

RESUMEN

The concept of paragenome is proposed, which is considered as a transient array of short DNA molecules appearing on the chromosome surface during development for the control of genome. The paragenome consists of printomeres, chronomeres, and phylomeres. Chronomeres and printomeres are obligatory for cells of certain differentiation lineages, but the cells of different lineages differ in the sets of these organelles. Phylomeres are facultative, since they appear only when development is modified. The paragenome is a system governing the chromatin configuration and level of structural genes expression, ensuring the interpretation of positional information by the cells and their differentiation in regulatory morphogenesis, and controlling the development in time. Deciphering of the paragenome will allow realization in future of direct reprogramming of somatic cell nuclei without using stem cells and eggs.

Asunto(s)

RESUMEN

The redusome hypothesis of aging and the control of biological time in individual development is proposed. Redusomes are hypothetical perichromosomal particles arising in differentiation events during morphogenesis of an organism. The linear molecule of DNA covered with proteins in the redusome is assumed to be a copy of a segment of chromosomal DNA. Redusomes are located mainly in subtelomeric regions of chromosomes. The redusome does not leave the body of a chromosome even in the course of cellular divisions, being kept in its chromosomal nest. Like telomeric DNA, redusome linear DNA is shortened step by step. Thus, tiny redusomes progressively decrease in size; it is from here their name originates. Together with loss of the length of DNA in a redusome, the number of different genes contained in it also decreases. Shortening of the redusomal DNA molecules (and, coupled to it, changes of the sets of genes in redusomes) is responsible for age-dependent shifts in the level of expression of different chromosomal genes. Owing to this, redusome DNA shortening serves as a key means of measuring biological time in individual development. The main part of DNA of most redusomes is postulated to be occupied by noncoding genes. Low-molecular-weight RNAs (micro RNAs and fountain RNAs, or fRNAs) are assumed to be transcribed from them. These RNAs are involved in regulation of various chromatin repackings that are specific to certain differentiations, while others modulate the levels of expression of chromosomal genes. Hypothetical fountain RNAs can quantitatively regulate the expression levels of chromosomal genes, forming specific complexes with fions. Fions are suggested to be specific sites of a chromosomal DNA which are complementary to different fRNAs. Fions reside in the vicinity of usual chromosomal genes. A complex of the fRNA-fion, specifically interacting with a closed gate of the corresponding ion channel of the internal nuclear membrane, initiates the opening of the gate for a very short time, thus organizing activity of an ion fountain which appears to be automatically aimed at the chromosomal gene nearest to the fion involved. The ion fountain creates, depending on specificity of matching fRNA, fion, and ion channel, a distinctive ionic environment near certain structural genes. Ion fountains exert their action on the configuration of corresponding segments of chromatin and on the transcriptional efficiency of chromosomal genes in a topographically specific manner. Hence, the fountain system of the nucleus is able to regulate the quantitative traits both of cells and organism; it can control dominance of alleles and plays a role in individual development. Significant and escalating truncation of the redusome DNA causes cell aging due to an arising and increasing deficit of fRNAs and, for this reason, the lack of required ions near certain structural genes. Progressive shortening of DNA of redusomes is proposed to result in cellular aging because of a constantly growing shortage of low-molecular-weight RNAs transcribed from redusomal genes. Two types of redusomes are postulated: chronosomes and printosomes. Linear molecules of DNA in these two types of redusomes are called chronomeres and printomeres, respectively. Chronosomes are responsible for measurement of biological time in nondividing cells of the CNS. Printosomes remember positions of cells in the course of interpretation of the positional information in morphogenesis. In accordance with the position of a cell in a morphogenetic field, printomeres do change cellular properties and remember the change made (this is a so-called printomere mechanism of interpretation of positional information). Besides, printomeres participate in maintaining the achieved state of cellular differentiation. Normally, the chronomere is shortened only on the maximum of infradian hormonal rhythm (T-rhythm) which initiates the act of a superhigh velocity of its transcription that is finished with truncation of the end of a chronomere (an effect called scrupting). Theprintomere can be shortened due to the effect of DNA end underreplication and owing to scrupting. The effect of the end underreplication of DNA in doubling cells occurs simultaneously both in printomeres and telomeres. Shortening of telomeres is just a bystander process of aging of cells, whereas the true cause of biological aging is only the shortening of redusome DNA. Processing of certain redusomes in terminally differentiating cells is a cause of a proliferation arrest. Linkage of genes in a eukaryotic chromosome is determined by the distances between genes and redusomes.

Asunto(s)

RESUMEN

The redusome hypothesis of aging and biological age control (Olovnikov, Biochemistry (Moscow) 2003, vol. 68, pp. 2-33; http://protein.bio.msu.su/biokhimiya/contents/v68/ToC6801.htm.) is discussed. Though the main part of telomere-related predictions (Olovnikov, 1971, 1973) have successfully been confirmed (end under-replication of linear DNA molecules; explanation why bacterial genome is circled to avoid this problem; telomerase existence in sex and cancer cells; correlation of telomera shortening with the number of cell doublings already performed by somatic cells that divide and age in vitro), I state that telomere model of cell aging should be abandoned, since a telomere-dependent signal of cellular senescence does not exist. Instead, it is postulated that so called redusomes are involved in control of biological time and aging. Redusomes are postulated nuclear organelles which are presented by small linear double helix DNA molecules of different specificities which are covered by proteins and located at special chromosomal nests. Each redusome has its own ori for replication, as well as promoter for transcription, but it has no centromere. Hence redusomes are distributing in mitoses among daughter cells only due to the behavior of chromosomes as their specific carriers. Transcripts from redusomes (both micro RNAs and so called fountain RNAs) participate in chromatin remodeling and chromosomal structural genes expression. Regular and consecutive losses of repeated genes from chronomeres (DNA of redusomes of neuroendoclinal and neurotrophic cells of a brain) are perceived by cells of brain's biochronometer as a course of biological time. Continuation of shortening of redusomal DNA molecules in the organism that has already achieved its physiological maturity is responsible both for cellular senescence and the organism aging. Telomere attrition is only a bystander process of aging, while the genuine cause of the cell and organism aging is the redusome DNA shortening.

Asunto(s)

RESUMEN

It is hypothesized that gene function is modulated through the action of the ion channels of the internal nuclear membrane, and that this underlies the phenomenon of dominance and some epigenetic effects. The topographic specificity essential to gene regulation by injecting portions of ions--ion fountains--is ensured by special fountain RNAs (fRNAs), which operate as double-stranded molecules, and fions, the fRNA-binding sites on the DNA. Every specific fion.fRNA complex then binds with the protein of an ion channel in the inner nuclear membrane, whereby this channel briefly opens to dispense, e.g., Ca2+, Zn2+, or K+ from the perinuclear cistern into the nucleus, as defined by the specificity of fRNA, fion, and the channel chosen by them. Fions may be situated both in introns of genes and at their flanks, even quite far from the target gene. Allelic fions, that is, fions located in homologous sites of homologous chromosomes but differing in the capacity of binding different fRNAs, will unequally influence the ionic surroundings of their structural genes. Ion channels can provide the dominant allele with an ionic atmosphere dissimilar from that of the recessive allele. Distinctions in the nature, number, and location of fions may be the main reason why the dominant and recessive alleles of a structural gene differ in activity even though their other properties are identical. Unequal changes occurring in the vicinity of the alleles may involve chromatin configuration, transcriptional activity of the gene, mRNA processing and lifespan. Isolation of structural genes in a chromosome by long intergene spacers, and large distances between chromosomes in the nucleus prevent undesirable interference of ion fountains. Fions may be key components of many enhancers and silencers. The performance of fions may be affected by pairing of homologous nucleotide sequences of chromosomes, which generates a number of epigenetic effects, such as transvection and gene position effect. Excessive approach of a structural gene to inadequate ion fountains may cause unscheduled chromatin compaction and gene suppression.

Asunto(s)

Asunto(s)

RESUMEN

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 which 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 so-called 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" (A. M. Olovnikov (1997) Int. J. Dev. Biol., 41: 923-931; A. M. Olovnikov (1999) J. Anti-Aging Medicine, 2: 57-71; A. M. Olovnikov (1999) Advances in Gerontology (St. Petersburg), 3: 54-64). 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.

Asunto(s)

RESUMEN

It is proposed that hypermutation of the Ig gene is based on the use of "misprimers" (MPs) capable of competing with a true primer for the DNA. The MP is a product of the cleavage of the nascent transcript. Each MP has an erroneous base on its 3; terminus. Wobbling of the unpaired 3; end of the MP forces the DNA polymerase to make an error.

Asunto(s)

RESUMEN

A fountain mechanism of quantitative regulation of gene expression level during development is proposed. The mechanism is based on postulated ability of a special class of RNA molecules, so called fountain RNAs (fRNAs), to induce passive and selective ionic channels in the internal nuclear membrane. Ions diffuse via channel from the nuclear lumen into the chromatin compartment. An RNA-dependent battery of ion channels is assumed to produce <> of ions in close vicinity to the corresponding genes. An ion atmosphere, in its turn, locally changes the chromatin configuration and effectiveness of transcription and processing of transcripts. Hence this mechanism can be used to change genes productivity. It is a basic mechanism of quantitative traits regulation. A passive selective ion flux periodically stops after a threshold ion concentration induces local chromatin compactization and arrests the activity of ion channels in a given chromatin compartment. This process serves as a basis for many cellular biorhythms that are relatively temperature-independent because of the passive nature of ion channel. It is postulated that eukaryotes became eukaryotes just to obtain this fountain mechanism that allows them to perform gradual quantitative modulation of corresponding genes expression levels. The fountain mechanism is partly responsible for dominance and heterosis, X-chromosome inactivation, gene position effects, and some other epigenetic events. It plays an important role in embryonic and post-embryonic development. A significant portion of the former <> DNA can be referred to as fDNA involved in the proposed mechanism functioning. Genomic rearrangements of fDNA could lead to micro- and macroevolutionary changes in the animal and plant kingdoms. The pivotal evolutionary function of transposons could reside in their ability to contain and relocate fDNA along the chromosomes.

RESUMEN

A molecular mechanism of reading of positional information by cells in morphogenesis and regeneration is proposed. It permits to translate the genome information into three-dimensional form of an organism. In the mechanism, a new fraction of DNA, so called "location DNA" is used which is suggested as a substitution instead of a former "egoistic" DNA. Domains, that are formed by this DNA and packed by lipid-containing bridges, are selectively unpacking in the gradient of inductor, the concentration of which positively correlates with the production of free radicals in the cells. Free radicals induce a selective destruction of lipid bridges which are variable in their resistance to the oxidative destruction. Hence the domains of location DNA are selectively decomactizing and activiting after bridge's elimination. In this way, a reading of positional information is performed. An epigenetic memory concerning the cellular determination state, that was already achieved, is based on the so called process of triplexation, the essence of which is a triplex formation, between signal RNA molecule and nascent double stranded DNA. A triplex is formed during the lagging strand synthesis or in the course of DNA repair synthesis. A telomeric element of postmitotic neurons, so called chronomere, assists to the organism in measuring of the flow of biological time, while chronomere length is an indicator of biological age of the organism.

Asunto(s)

RESUMEN

In 1971 I published a theory in which I first formulated the DNA end replication problem and explained how it could be solved. The solution to this problem also provided an explanation for the Hayflick Limit, which underpins the discovery of in vitro and in vivo cell senescence. I proposed that the length of telomeric DNA, located at the ends of chromosomes consists of repeated sequences, which play a buffer role and should diminish in dividing normal somatic cells at each cell doubling. I also proposed that the loss of sequences containing important information that could occur after buffer loss could cause the onset of cellular senescence. I also suggested that for germline cells and for the cells of vegetatively propagated organisms and immortal cell populations like most cancer cell lines, an enzyme might be activated that would prevent the diminution of DNA termini at each cell division, thus protecting the information containing part of the genome. In the last few years, most of my suggestions have been authenticated by laboratory evidence. the DNA sequences that shorten in dividing normal cells are telomeres and the enzyme that maintains telomere length constant in immortal cell populations is telomerase.

Asunto(s)

Asunto(s)

RESUMEN

A possible effect of incomplete terminal DNA repair providing for shortening of telomeric DNA in the somatic cells, specifically postmitotic neurons, has been discussed. The effect of incomplete terminal repair can and must show up independently from the effect of incomplete terminal DNA replication proposed earlier.

Asunto(s)

RESUMEN

Incomplete repair of the DNA double helix terminus is an independent mechanism of the telomeric DNA shortening in non-dividing cells. This effect of incomplete terminal DNA repair may initiate aging of postmitotic neuroendocrine cells or even whole postmitotic organisms, if loss of the buffer telomeric DNA (due to incomplete terminal repair) is followed by the loss of significant information in the nucleotide sequences. We also consider a possibility of local aging of a cell group, e.g., in the locomotor system where extreme physical load favors accumulation of nuclear factors inducing accelerated shortening of telomeric DNA.

Asunto(s)

Asunto(s)