From Big Medical Encyclopedia

REPARATION OF GENETIC DAMAGES (Latin reparatio recovery) — recovery of biological activity of the damaged genetic structures. Of the item at molecular level understand recovery of primary and secondary structure of the damaged molecules DNA as R., at the genetic level — elimination of premutational changes, at the cellular level — elimination of the damages leading to reproductive death of a cell. The river of of the item is of great importance in a pathogeny of a number of diseases, including tumoral as between mutagenesis (see) and carcinogenesis (see) there is close connection. The increased frequency of a malignancy of cells with defects of DNA repair is established at hereditary diseases (see). Also hereditary diseases are known, at to-rykh these or those ways of R. of of the item are damaged. Especially well are in this respect studied a pigmental xeroderma (see. Xeroderma pigmental ), Fankoni's anemia (see. Hypoplastic anemia ), an ataxy teleangiectasia (see. Ataxy ), Blum's syndrome (see. Poikiloderma ); are in a stage of a research a Down syndrome (see. Down disease ), Kokkeyn's syndrome (see. Ichthyosis ), progeria (see) and some other. R.'s weakening of the item is noted and at the caused diseases nek-ry partially hereditarily, generally rheumatic nature — collagenic diseases (see), in particular at to a lupus erythematosus (see) and pseudorheumatisms (see). The available data on a role of a reparation of genetic damages to processes of aging have contradictory character.

R. of the item is the fullest it is studied on prokariotny organisms (see). The research P. of of the item is conducted preferential in the following directions: a research of pattern of death of cells or emergence of the inherited changes — mutations (see. Mutation ), receiving and the analysis of the mutations influencing R.'s process of the item, allocation and a research of the enzymes participating in a reparation of genetic damages.

Frequency of emergence of genetic damages is so high that in the absence of R. of the item the number of damages, a cut arises at a natural background of mutagens, would lead of an organism to death. Cells are potentially capable to be recovered after damages of genetic material of all types.

The river of of the item is provided with tens of enzymes, many from to-rykh participate also in processes replications (see) and recombinations (see). Allocate seven basic groups of the enzymes providing R. to of the item: nucleosidases (see), the molecules DNA catalyzing a vyshchepleniye of nitrogen bases by a rupture of N-glycosidic linkages without disturbance of a sakharofosfatny skeleton with formation of apurinovy and apirimidinovy sites of DNA (AP-websites); the insertaza which are building in nitrogen bases the AP-websites; lyase, carrying out splitting of the formed pirimidinovy dimer; the endonucleases which are carrying out incision (incision) of a polynucleotide chain near the damaged place and the ekzonukleaza making removal (excision) of the damaged site (see. Nucleases ); DNK-ttolimerazy (see. Polymerases ), carrying out building of the formed gaps; DNA-ligases sewing free 3 '-and 5 '-the ends of a polynucleotide chain (see. Enzymes ).

On a source of the used genetic information molekulyarnogenetichesky mechanisms P. of of the item can be divided into three groups:

1) DNA repair without use of information on the sequence of nucleotides in a polynucleotide chain; 2) River of of the item with use of such information, i.e. with use of complementary intact thread as matrixes; 3) River of of the item with use of intermolecular information on the sequence of nucleotides in a homologous polynucleotide chain.

First of all photoreactivation (photoreversion) consisting in zymolysis of the pirimidinovy dimer who are formed at action of Uv-radiation concerns to the first group of mechanisms P. of of the item. Process of photoreactivation proceeds only at effect of visible light (maximum efficiency for different enzymes and substrates note in the field of lengths of waves apprx. 400 nanometers) and with participation fotoliaz. Photoreactivation plays the known role also at actions of ionizing radiation of high energy. Along with enzymatic photoreactivation non-enzymatic photochemical recovery of the damaged DNA, in vitro observed, e.g., at the transforming DNA, and also so-called photoprotection is known: the growth inhibition at strong lighting favoring to implementation of other reparative systems. It is necessary to carry a reparation of single ruptures of a sakharofosfatny skeleton of molecule DNA by means of sewing together of the formed ends of DNA-ligase to the same group of mechanisms P. of of the item. Information on the nucleotide sequence in a polynucleotide chain of the second DNA thread is not used. Intact second thread plays purely mechanical role, holding the free ends of the broken-off DNA thread in close proximity from each other.

It is necessary to notice that cells have at the order and other mechanisms of a reparation of dimer and single-stranded gaps.

River of and. without use of information on the sequence of nucleotides in a polynucleotide chain of complementary thread it can be carried out by modification of nek-ry nitrogen bases; e.g., with the help transmetilaz from them «excess» methyl groups are chipped off. Other way of a reparation of the damaged bases also without use of information concluded in the polynucleotide sequence of complementary thread as matrixes consists in eliminating of the damaged or changed nitrogen base and replacement its normal with participation DNK-glikozidazy and insertaza.

Among mechanisms P. of of the item, the complementary thread as a matrix which is carried out with use, the greatest value has the mechanism of a so-called ekstsizionny reparation, at a cut the site of the damaged DNA thread is removed and the formed gap is built up with nucleotides, complementary to nucleotides of the unimpaired thread. The dark reparation of pirimidinovy dimer is most studied. This process consists of four stages: 1) incisions: endonuclease finds dimeasures and makes near it a cut of polynucleotide thread; 2) excisions: the ekzonukleaza deletes the damaged site of thread; 3) reparative synthesis: DNA polymerases fill the formed gap, using complementary intact thread as a matrix; 4) connections of again synthesized site with a core thread by means of ligases. At bacteria of a gap in DNA threads are built up either short (up to 30 nucleotides long), or long sites (up to 1500 nucleotides long). The mutant called «reckless» at to-rogo on everyone dimeasures is known 27 000 nucleotides vyshcheplyatsya on average. Building of gaps by long sites of nucleotides after cutting of dimer is not found in mammals. Absolutely there is also an ekstsizionny reparation at other changes of primary structure of DNA (emergence of iyesiarenny nitrogen bases, the AP-websites, adducts, etc.), at the same time the specific endonucleases distinguishing the corresponding damages participate in R. of the item. The single-stranded gaps especially characteristic of action of ionizing radiation, are also liquidated by means of an ekstsizionny reparation. As damage consists in a cut of thread, the first link of the mechanism of an ekstsizionny reparation — incision — is absent. At bacteria and at the person the mutants not capable to an ekstsizionny reparation of dimer are known endonucleases-nye, but the reparation of single-stranded gaps at them occurs normally. Formation of only very small gaps in 1 — 2 nucleotide is characteristic of an ekstsizionny reparation of single-stranded gaps.

At the bacteria not capable vyshcheplyat dimeasures, replikativny synthesis of new threads consists in formation of short fragments, length to-rykh corresponds to distance between dimeasures. Nevertheless such bacteria keep viability in the presence in their genome of tens of dimer since at the subsequent incubation in a medium the molecular weight (weight) of new threads reaches a normal amount at the expense of a so-called postreplikativny reparation. The reparation of the gaps which resulted from defective synthesis occurs by a recombination between maternal and affiliated threads; after a recombination the gap appears opposite to the unimpaired site and is filled with the corresponding nucleotides by reparative synthesis. Besides, the mechanism of a postreplikativny reparation without recombination is known: new threads are synthesized bypassing damages. Such reparation is especially characteristic of mammals, its molecular mechanism is not studied yet. Synthesis of normal threads at unextracted damages can happen to the help of a so-called replikativny reparation also. Damage to parent thread blocks synthesis of new thread while on the complementary unimpaired thread it proceeds. At the shift of a so-called replicative fork (see. Replication ) in the opposite direction with release of complementary affiliated threads of unequal length they form duplex and in short thread there is a building of the site, complementary to damaged.

The third group of molecular and genetic mechanisms — R. of the item proceeding with use of genetic information from homologous molecule DNA takes place in case of damages with involvement of all section of molecule DNA. First of all it concerns double-stranded ruptures of a sakharofosfatny skeleton of DNA, i.e. damages, the most essential for biol. actions of ionizing radiation. It is experimentally proved that the reparation of double gaps occurs only in the presence in a cell not less than two copies of genetic material. So, in experiences on yeast, chromosomes to-rykh contain on one molecule DNA, at radiation of normal diploids there is a reparation of double gaps. At radiation of haploids in a stationary growth phase there is no reparation, but it is observed at radiation in a phase of logarithmic growth when in a cell the second copy of a genome appears. Among bacteria the reparation of double gaps takes place at a micrococcus, to-ry is polyploid. At colibacillus the reparation of double gaps does not happen to one genome, but it is observed in cells with several nucleoids. The reparation of double gaps is absent in cells, at to-rykh as a result of a mutation ability to a recombination is broken. It indicates the rekokhmbinatsionny mechanism of a reparation of double gaps; details it are not studied. The reparation of cross stitchings of DNA happens by a vyshchepleniye of a stitching, a recombination to the unimpaired homolog and buildings of a gap with use of information obtained from the unimpaired threads.

Not enough attention as in genetics idea of a one-filamentous structure of chromosomes dominated was paid before to studying of mechanisms P. of of the item with participation of homologous molecules. It is possible that similar mechanisms P. of of the item are widespread more widely. It is possible to assume that at mammals interaction of homologs takes place at a postreplikativny reparation bypassing damages. The mechanism of this process remains still not clear.

All mechanisms P. of of the item in a cell are repeatedly duplicated and can go different ways. These ways are under difficult genetic control. Thanks to it survival of mutant cells, defective on any enzymes of a reparation, is provided with inclusion of reserve ways. It is known that mutagen factors are capable to induce reparative processes in cells. So, survival UF-obl of a scientific bacteriophage, to-ry it is deprived of reparative enzymes, but not deprived of ability to induce fagospetsifnchny enzymes of a reparation in a bacterium at the expense of what there is its recovery, significantly increases if it is replicated in UF-obluchennykh bacteria (so-called UV-reactivation). Presence at cells of reparative systems, active in normal conditions (constitutive), and the systems joining at action of high doses of mutagens (indutsibelny) is obvious.

All main types P. of of the item have constitutive and indutsibelny branches. Molecular mechanisms of induction of R. of of the item are studied a little. It became known of a role in this process of a poli-ADF-ribozy. Its synthesis is carried out with the participation of the enzyme which is activated with the advent of gaps in DNA; the formed poln-ADF-riboza, connecting to DNA, changes its conformation and by that makes available for enzymes of a reparation.

Accuracy of different mechanisms P. of of the item is not identical. So, photoreactivation or an ekstsizionny reparation with building of gaps by short sites of nucleotides carry out R. of the item almost unmistakably. At an ekstsizionny reparation with building by long sites of nucleotides and at an indutsibelny postreplikativny reparation (so-called. SOS-reparations) often there is a wrong embedding of nucleotides that leads to formation of mutants. Between indutsibelny and mutagen R. of the item there is an expressed correlation though there are also exceptions.

Cells are capable to reparirovat damages, both premutational, and lethal for a cell. As the genetic device of prokariot consists of one molecule DNA, for them all three aspects of a reparation — the phenomenon of one order, and communication between them is obvious. As for eukaryotes, researches P. of of the item at all three levels were still conducted almost independently from each other. The fact that the same mechanisms are the cornerstone of the phenomena of a reparation is not subject to doubt, but there is no unambiguous communication between them. The reparation of genovariations at eukaryotes was almost not investigated. The reparation of the damages which are the cornerstone of structural mutations is found at increase in a time slice between a cart

action of a mutagen and cell division when premutational change passes into an irreversible form. It is established that, as well as at R. and. at molecular level, R. and. chromosomes happens constitutive and indutsibelny and that indutsibelny R. of the item more mutagen. However R. of the item of chromosomes does not come down to a reparation of elementary molecular damages. At a research of distribution of structural mutations on cells it was established that R. results from of the item at eukaryotes not only the mechanisms considered above but also at the level of supramolecular potential genetic damages. However such R.' mechanism of of the item is not studied at all. During the studying of effects of mutagens, lethal for a cell, distinguish a reparation so-called subletaly and potential details. The first find in experiments on the fractioned impact of a mutagen on a cell, the second — at incubation of cells in suboptimal conditions.

Whether have two types of damages and respectively mechanisms of their reparation the different nature or their distinction it is connected only with a technique of detection, not clearly. There are also no data allowing to connect unambiguously damages, premutational and lethal for cells, with specific mechanisms P. of of the item at molecular level.

Thus, R. of the item has crucial importance for biol. effects DNK-tropnykh of the damaging agents and for emergence of mutations.

Bibliography: E. E Ganass. Radiation damage and reparation of chromosomes, M., 1976; V. D Tinmen. DNA repair and its biological value, L., 1979; Korogodin V. I. Problems of post-radiation recovery, M., 1966; Archer N. V. Biofizika of cytogenetic damages and genetic code, L., 1968; Modern problems of radiobiology, under the editorship of. A. M. Kuzina, t. 1, M., 1970; Molecular mechanisms for repair of DNA, ed. bv P. C. Hanawalt a. R. B. Setlow, N. Y. — L., 1975; Repair from genetic radiation damage, and differential radiosensitivity in germ cells, ed. by F. H. Sobels, Oxford a. o., 1963.

H. V. Luchnik.