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Reparation: what is it? DNA repair mechanisms. DNA repair systems: general information Biological role and biochemical mechanisms of repair




Discovery history

Single-strand and double-strand DNA damage

Sources of DNA damage

  • UV radiation
  • Chemical substances
  • DNA replication errors
  • Apurinization - cleavage of nitrogenous bases from the sugar-phosphate backbone
  • Deamination - cleavage of an amino group from a nitrogenous base

Main types of DNA damage

  • Single nucleotide damage
  • Damage to a pair of nucleotides
  • DNA chain break
  • Formation of cross-links between the bases of the same strand or different strands of DNA

The device of the reparation system

Each of the reparation systems includes the following components:

  • an enzyme that "recognizes" chemically altered sections in the DNA chain and breaks the chain near the damage
  • an enzyme that removes the damaged area
  • an enzyme (DNA polymerase) that synthesizes the corresponding section of the DNA chain to replace the deleted one
  • an enzyme (DNA ligase) that closes the last bond in the polymer chain and thereby restores its continuity

Types of reparation

Excision repair

excisional repair precision- excision) includes the removal of damaged nitrogenous bases from DNA and the subsequent restoration of the normal structure of the molecule.

Notes


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DNA synthesis occurs by a semi-conservative mechanism: each strand of DNA is copied. Synthesis occurs in sections. There is a system that eliminates errors in DNA reduplication (photoreparation, pre-reproductive and post-reproductive repair). The reparation process is very long: up to 20 hours, and complicated. Enzymes - restriction enzymes cut out an inappropriate section of DNA and complete it again. Repairs never proceed with 100% efficiency, if it did, evolutionary variability would not exist. The repair mechanism is based on the presence of two complementary chains in the DNA molecule. The distortion of the nucleotide sequence in one of them is detected by specific enzymes. Then the corresponding site is removed and replaced by a new one, synthesized on the second complementary DNA strand. This reparation is called excisional, those. with cutout. It is carried out before the next replication cycle, so it is also called pre-replicative. In the event that the excision repair system does not correct a change that has arisen in one DNA strand, this change is fixed during replication and it becomes the property of both DNA strands. This leads to the replacement of one pair of complementary nucleotides with another or to the appearance of breaks in the newly synthesized chain against the changed sites. Restoration of the normal DNA structure can also occur after replication. Post-reply reparation is carried out by recombination between two newly formed double strands of DNA. During pre-replicative and post-replicative repair, most of the damaged DNA structure is restored. If in the cell, despite the ongoing repair, the amount of damage remains high, the processes of DNA replication are blocked in it. Such a cell does not divide.

19. Gene, its properties. Genetic code, its properties. Structure and types of RNA. Processing, splicing. The role of RNA in the process of realization of hereditary information.

Gene - a section of a DNA molecule that carries information about the structure of a polypeptide chain or macromolecule. The genes of one chromosome are arranged linearly, forming a linkage group. DNA in the chromosome performs different functions. There are different sequences of genes, there are sequences of genes that control gene expression, replication, etc. There are genes that contain information about the structure of the polypeptide chain, ultimately structural proteins. Such sequences of nucleotides one gene long are called structural genes. Genes that determine the place, time, duration of the inclusion of structural genes are regulatory genes.

Genes are small in size, although they consist of thousands of base pairs. The presence of a gene is established by the manifestation of the trait of the gene (final product). The general scheme of the structure of the genetic apparatus and its work was proposed in 1961 by Jacob, Monod. They proposed that there is a section of the DNA molecule with a group of structural genes. Adjacent to this group is a 200 bp site, the promoter (the site of adjunction of DNA-dependent RNA polymerase). The operator gene adjoins this site. The name of the whole system is operon. Regulation is carried out by a regulatory gene. As a result, the repressor protein interacts with the operator gene, and the operon begins to work. The substrate interacts with the gene regulators, the operon is blocked. Feedback principle. The expression of the operon is turned on as a whole.

In eukaryotes, gene expression has not been studied. The reason is serious obstacles:

Organization of genetic material in the form of chromosomes

In multicellular organisms, cells are specialized and therefore some of the genes are turned off.

The presence of histone proteins, while prokaryotes have “naked” DNA.

DNA is a macromolecule; it cannot enter the cytoplasm from the nucleus and transmit information. Protein synthesis is possible due to mRNA. In a eukaryotic cell, transcription occurs at a tremendous speed. First, pro-i-RNA or pre-i-RNA appears. This is explained by the fact that in eukaryotes, mRNA is formed as a result of processing (maturation). The gene has a discontinuous structure. The coding regions are exons and the non-coding regions are introns. The gene in eukaryotic organisms has an exon-intron structure. The intron is longer than the exon. In the process of processing, introns are "cut out" - splicing. After the formation of a mature mRNA, after interacting with a special protein, it passes into a system - the informosome, which carries information to the cytoplasm. Now exon-intron systems are well studied (for example, oncogene - P-53). Sometimes the introns of one gene are exons of another, then splicing is not possible. Processing and splicing are able to combine structures that are distant from each other into one gene, so they are of great evolutionary importance. Such processes simplify speciation. Proteins have a block structure. For example, the enzyme is DNA polymerase. It is a continuous polypeptide chain. It consists of its own DNA polymerase and endonuclease, which cleaves the DNA molecule from the end. The enzyme consists of 2 domains that form 2 independent compact particles linked by a polypeptide bridge. There is an intron at the border between two enzyme genes. Once the domains were separate genes, and then they got closer. Violations of such a gene structure leads to gene diseases. Violation of the structure of the intron is phenotypically imperceptible, a violation in the exon sequence leads to mutation (mutation of globin genes).

10-15% of RNA in a cell is transfer RNA. There are complementary regions. There is a special triplet - an anticodon, a triplet that does not have complementary nucleotides - GHC. The interaction of 2 subunits of the ribosome and mRNA leads to initiation. There are 2 sites - pectidyl and aminoacyl. They correspond to amino acids. Synthesis of the polypeptide occurs step by step. Elongation - the process of building a polypeptide chain continues until it reaches a meaningless codon, then termination occurs. The synthesis of the polypeptide ends, which then enters the ER channels. The subunits separate. Different amounts of protein are synthesized in a cell.

Provides self-copying of genetic material. At the same time, due to the principle of complementarity, the accuracy of matching the nucleotide sequences of the daughter chain to the template one is very high. In addition, DNA is a fairly chemically inert substance, which ensures its greater stability compared to, for example, RNA. However, this is not enough, since DNA can still be damaged by external influences, and errors can also occur at the replication stage. Therefore, mechanisms must exist in cells to correct damage and synthesis errors, i.e., DNA repair.

There are a number of repair mechanisms that are performed at different stages of DNA synthesis, and also depending on the type of errors that occur.

All together, repair mechanisms significantly reduce the frequency of errors in DNA molecules and are aimed at maintaining the stability of the hereditary material. However, since not all changes in the structure of DNA are eliminated, mutations occur, due to which a variety of living organisms arose on Earth.

Elimination of errors by DNA polymerase

First of all, DNA polymerase itself, when growing a new DNA chain, checks whether the right nucleotide is attached to the growing thread.

There are altered forms of nitrogenous bases that can complementary bind to template nucleotides. So an altered form of cytosine can bind to adenine. The polymerase will add this final nucleotide to the growing chain, but it will quickly turn into its usual form - it will become ordinary cytosine. In this case, hydrogen bonds are destroyed (because complementarity is violated), and an unpaired nucleotide is obtained at the end, but covalently connected to the synthesized chain. The polymerase can no longer grow the chain. The polymerase itself or its associated enzyme editing endonuclease cleave off the last "wrong" nucleotide.

As a result of this self-correcting mechanism, the frequency of replication errors is reduced by a factor of 10. If the attachment of an erroneous nucleotide at the stage of DNA synthesis is 10 -5 , then the repair activity of the polymerase reduces their number to 10 -6 .

Reparation mechanisms

DNA polymerase corrects some of the replication errors, but not all. In addition, changes in the DNA nucleotide sequence also occur after its duplication. Thus, purine bases (adenine and guanine) can be lost, cytosine is deaminated, turning into uracil. These and other changes usually occur due to certain chemically active substances contained in the environment surrounding the chromosome. A number of such compounds disrupt normal base pairing. Under the action of ultraviolet radiation, two adjacent thymine residues can form bonds with each other, thymine dimers appear.

Exists direct reparation when, if possible, the original structure of the nucleotides is enzymatically restored, without cutting them out.

Excision repair

Excisional, or pre-replicative, repair is carried out before the next replication cycle.

There is a class of enzymes that detect altered nucleotide sequences in one of the complementary DNA strands. After that, the erroneous section is removed and replaced with a newly synthesized one. In this case, the site of the complementary “correct” thread serves as a matrix.

Repair enzymes usually detect errors on the new strand of DNA, not the template. There is a slight difference between the two strands of one DNA molecule, which consists in the degree of methylation of the nitrogenous bases. In the daughter chain, it lags behind the synthesis. Enzymes recognize such a chain and it is on it that they correct sections that are in one way or another not complementary to sections of the old chain. In addition, ruptures of the strand, which in eukaryotes is synthesized by fragments, can serve as signals.

Enzyme endonuclease able to detect the loss of purine bases. This enzyme breaks the phosphoester bond at the site of injury. The next step is the enzyme exonuclease, which removes the portion that contains the error. After that, the hole is built according to the complementarity of the matrix.

DNA glycosylases- a whole class of enzymes that recognize DNA damage as a result of deamination, alkylation and other structural changes in its bases. Glycosylases remove bases, not nucleotides. After that, sections of the DNA strand without bases are repaired in the same way as in the "repair" of purines.

It should be noted that deamination of nitrogenous bases can lead to the impossibility of restoring the original nucleotide sequence. There is a replacement of some base pairs with others (for example, C-G will be replaced by T-A).

Enzymes that remove sites with thymine dimers recognize not individual erroneous bases, but more extended sections of altered DNA. Here, too, the removal of the site and the synthesis of a new one in its place takes place. In addition, thymine dimers can be eliminated spontaneously by exposure to light - the so-called light repair.

Post-replicative repair

If pre-replicative repair has not corrected the altered DNA regions, then they are fixed during replication. One of the daughter DNA molecules will contain changes in both of its strands. In it, some pairs of complementary nucleotides are replaced by others, or gaps appear in the newly synthesized chain opposite the altered sections of the matrix.

The post-replicative repair system is able to recognize such DNA changes. At this stage, the elimination of DNA damage is carried out by the exchange of fragments (i.e., recombination) between two new DNA molecules, one of which contains damage, the other does not.

This is the case for thymine dimers that were not removed in the previous steps. There are covalent bonds between two adjacent thymines. Because of this, they are unable to hydrogen bond to the covalent chain. As a result, when a daughter strand is synthesized on the template strand containing the thymine dimer, a gap is formed in it. This gap is recognized by repair enzymes. It is clear that this DNA molecule does not have a correct section (one strand contains a thymine dimer, the other contains a hole). Therefore, the only way out is to take a piece of DNA from a "healthy" molecule, which is taken from the template chain of this DNA molecule. The hole formed here is filled according to the principle of complementarity.

SOS system

A significant part of DNA damage is eliminated using the described repair mechanisms. However, if there are too many errors, then the so-called SOS system usually turns on, consisting of its own group of enzymes that can fill holes without necessarily observing the principle of complementarity. Therefore, the activation of the SOS system often causes mutations.

If the DNA change is too significant, then replication is blocked, and the cell will not divide.

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1 DNA REPAIR 1 Repair systems 1 Direct repair. Examples 2 Excision repair. Examples and types 3 Repair of DNA replication errors 4 Recombinant (post-replicative) repair in bacteria 5 SOS repair DNA repair systems are quite conserved in evolution from bacteria to humans and are best studied in E. coli. Two types of reparation are known: direct and excisional (from the English. Excision - cutting). Direct repair Direct repair is the simplest way to eliminate damage in DNA, which usually involves specific enzymes that can quickly (usually in one step) eliminate the corresponding damage, restoring the original structure of nucleotides. O6-methylguanine-DNA-methyltransferase 1. This is how, for example, O6-methylguanine-DNA-methyltransferase (suicide enzyme) acts, which removes the methyl group from the nitrogenous base to one of its own cysteine ​​residues. In E. coli, up to 100 molecules of this protein. The protein of higher eukaryotes, similar in function, obviously plays an important role in protection against cancer caused by internal and external alkylating factors. DNA insertase 2. AP sites can be repaired by direct insertion of purines with the participation of enzymes called DNA insertases (from the English insert - insert). photolyase 3. Thymine dimers are “opened” by direct reparation with the participation of photolyases, which carry out the corresponding photochemical transformation. DNA photolyases are a group of light-activated enzymes with a wavelength of nm (visible region), for which they have a special light-sensitive center in their structure. They are widely distributed in nature and found in bacteria, yeast, insects, reptiles, amphibians and humans. These enzymes require a variety of cofactors (FADH, tetrahydrofolic acid, etc.) involved in the photochemical activation of the enzyme. Photolyase E. coli

2 is a protein with a molecular weight of 35 kDa, tightly associated with an oligoribonucleotide with a length of nucleotides necessary for the activity of the enzyme. Examples of direct repair 1. The methylated base O6-mG is dimethylated by the enzyme methyltransferase O6-methylguanine-DNA methyltransferase (a suicide enzyme), which transfers a methyl group to one of its cysteine ​​residues 2. AP sites can be repaired by direct insertion of purines with the participation of enzymes called DNA insertases (from the English insert-insert). SCHEME OF EXAMPLE OF DIRECT DAMAGE REPAIR In DNA, the methylated base O6-mG is demethylated by the enzyme methyltransferase, which transfers the methyl group to one of its amino acid residues cysteine. Photolyase DNA attaches to the thymine dimer and, after irradiation with visible light, this dimer is expanded. Excision repair (from English excision - cutting). DEFINITION Excision repair involves the removal of damaged bases from DNA and the subsequent restoration of the normal structure of the molecule.

3 MECHANISM Several enzymes usually take part in excision repair, and the process itself affects not only the damaged nucleotide, but also its adjacent nucleotides. CONDITIONS A second (complementary) strand of DNA is required for excision repair. A general simplified scheme of excision repair is shown in Fig. STAGES The first step in excision repair is the excision of abnormal nitrogenous bases. It is catalyzed by a group of DNA-N-glycosylases - enzymes that cleave the glycosidic bond between deoxyribose and a nitrogenous base. IMPORTANT NOTE: 3 In humans, DNA-N-glycosylases have a high substrate specificity: different enzymes of this family recognize and cut out various abnormal bases (8-oxoguanine, uracil, methylpurines, etc.). In bacteria, DNA-N-glycosylase does not have such substrate specificity. base breaks the sugar-phosphate backbone of the DNA molecule in the AP site sequentially cleaves off several nucleotides from the damaged section of one DNA strand SPECIFIC SEQUENTIAL STEPS OF THIS MECHANISE: As a result of the action of DNA-N-glycosylases, an AP site is formed, which is attacked by the enzyme AP-endonuclease. It breaks the sugar-phosphate backbone of the DNA molecule in the AP site and thereby creates conditions for the work of the next enzyme - exonuclease, which sequentially cleaves off several nucleotides from the damaged section of one DNA strand.

4 WHAT HAPPENS NEXT: 4 In bacterial cells, the vacated space is filled with the appropriate nucleotides with the participation of DNA polymerase I, which targets the second (complementary) DNA strand. Since DNA polymerase I is able to extend the 3'-end of one of the strands at the break in double-stranded DNA and remove nucleotides from the 5'-end of the same break, i.e. carry out nick-translation, this enzyme plays a key role in DNA repair. The final stitching of the repaired sites is carried out by DNA ligase. In eukaryotic (mammalian) cells DNA excision repair in mammalian cells is accompanied by a sharp surge in the activity of yet another enzyme, polyADP-ribose polymerase. In this case, ADP-ribosylation of chromatin proteins (histones and non-histone proteins) occurs, which leads to a weakening of their connection with DNA and opens access to repair enzymes. The donor of ADP-ribose in these reactions is NAD+, whose reserves are greatly depleted during excisional repair of damage caused by X-ray irradiation: charges of these proteins and weakening their contact with DNA. WHAT IS A GROUP OF ENZYMES DNA glycosylase cleaves the glycosidic bond between deoxyribose and a nitrogenous base

5 which leads to excision of abnormal nitrogenous bases 5 DNA glycosylases involved in the elimination of oxidative damage to DNA in prokaryotic and eukaryotic cells are very diverse and differ in substrate specificity, spatial structure and methods of interaction with DNA. The most studied DNA glycosylases include: endonuclease III (EndoIII), amido pyrimidine DNA glycosylase (Fpg), Mut T and Mut Y of Escherichia coli. E. coli endonuclease III recognizes and specifically cleaves oxidized pyrimidine bases from DNA. This enzyme is a monomeric globular protein consisting of 211 amino acid residues (molecular weight 23.4 kDa). The gene encoding Endo III has been sequenced and its nucleotide sequence has been established. Endo III is an iron-sulfur protein [(4Fe-4S)2+-protein], which has an element of the supra-secondary structure of the "Greek key" type (helix - hairpin - helix), which serves to bind to DNA. Enzymes with similar substrate specificity and similar amino acid sequences have also been isolated from bovine and human cells. E. coli form amido pyridine-dna-glycosylase "recognizes" and cleaves oxidized heterocyclic bases of the purine series from DNA. EXCISION REPAIR SCHEME STAGE 1 DNA N glycosidase removes the damaged base AP endonuclease introduces a break in DNA EXCISION REPAIR SCHEME 1 DNA N glycosidase removes the damaged base AP endonuclease introduces a break in DNA 2 Exonuclease removes a number of nucleotides

6 3 DNA polymerase fills the vacant site with complementary mononucleotides DNA ligase crosslinks the repaired DNA strand 6 Mut T - a small protein with a molecular weight of 15 kDa, which has nucleoside triphosphatase activity, which preferentially hydrolyzes dgtp to dgmp and pyrophosphate. The biological role of Mut T is to prevent the formation of non-canonical A:G and A:8-oxo-G pairs during replication. Such pairs can appear when the oxidized form of dgtp (8-oxo-dGTP) becomes a substrate for DNA polymerase. Mut T hydrolyses 8-oxo-dGTP 10 times faster than dgtp. This makes 8-oxo-dGTP the most preferred Mut T substrate and explains its functional role. Mut Y is a specific adenine DNA glycosylase that cleaves the N-glycosidic bond between adenine and adenosine deoxyribose, which forms a non-canonical pair with guanine. The functional role of this enzyme is to prevent the T:A-G:A mutation by cleaving an intact adenine residue from the A:8-oxo-G base pair.

7 Nucleotide excision repair (ATP-dependent mechanism for DNA damage removal) Recently, in excision repair, special attention has been paid to the ATP-dependent mechanism for DNA damage removal. This type of excision repair is called nucleotide excision repair (NER). It includes TWO STAGES: 1. removal of oligonucleotide fragments containing damage from DNA and Excinuclease, an enzyme that removes DNA fragments 2. subsequent reconstruction of the DNA chain with the participation of a complex of enzymes (nucleases, DNA polymerase, DNA ligase, etc.). The removal of a DNA fragment occurs on both sides of the damaged nucleotide. The length of the removed oligonucleotide fragments differs between prokaryotes and eukaryotes. Removal of a DNA fragment in prokaryotes Thus, in E. coli, B. subtilus, Micrococcus luteus, a nucleotide-long fragment is cut out. Removal of a DNA fragment in eukaryotes, and in yeast, amphibians and humans - a fragment consisting of nucleotides. Excinuclease enzyme that removes DNA fragments The cleavage of a DNA fragment is carried out by the enzyme excinuclease (excinuclease). In E. coli, this enzyme consists of 3 different protomers uvra uvr B uvr C, each of which performs a specific function during excisional cleavage of a DNA fragment. These proteins are named after the first letters of the words "ultra violet repair". The uvr A protomer has ATPase activity, binds to DNA in the form of a dimer, carrying out the primary damage recognition and binding uvr B The uvr B protomer has: 1. Latent ATPase and latent helicase activity necessary for conformational changes and unwinding of the DNA double helix; 7

8 2. Endonuclease activity, cleaving the internucleotide (phosphodiester) bond from the 3' end of the cleaved fragment. Thus, the protomers uvr A, uvr B, uvr C interact with DNA in a certain sequence, carrying out an ATP-dependent reaction for the cleavage of an oligonucleotide fragment from the DNA strand being repaired. The resulting gap in the DNA molecule is repaired with the participation of DNA polymerase I and DNA ligase. A model of excision repair with the participation of the above enzymes is shown in Fig. Excision repairs in humans. Excision repairs in humans are also ATP-dependent and include three main stages: damage recognition, double cutting of the DNA strand, reparative synthesis, and ligation of the repaired strand. However, 25 different polypeptides are involved in human DNA excision repair, 16 of which are involved in the cleavage of the oligonucleotide fragment, being excinuclease protomers, and the remaining 9 carry out the synthesis of the repaired region of the molecule. In the DNA repair system in humans, transcription proteins RNA polymerase II and TFPN, one of the six main eukaryotic transcription factors, play a very significant role. It should be noted that excisional repair in prokaryotes, as well as in eukaryotes, depends on the functional state of DNA: transcribed DNA is repaired faster than transcriptionally inactive. This phenomenon is explained by the following factors: chromatin structure, strand homology of transcribed DNA regions, the effect of strand damage and its effect on RNA polymerase. IMPORTANT NOTE: ENCODING DNA CHAIN ​​(information storage chain) DNA MATRIX CHAIN ​​(information is written off from it) 8

9 Major damages such as the formation of thymine dimers are known to block transcription in both bacteria and humans if they occur on the DNA template strand (damages on the coding strand do not affect the transcription complex). RNA polymerase stops at the site of DNA damage and blocks the work of the transcription complex. 9 Transcription-repair linkage factor (TRCF). In E. coli, enhancement of transcriptional repair is mediated by one special protein, the transcription-repair linkage factor (TRCF). This protein promotes: 1. detachment of RNA polymerase from DNA 2. simultaneously stimulates the formation of a complex of proteins that repair the damaged area. At the end of the repair, RNA polymerase falls into place and transcription continues (see Fig.). So the general scheme of excisional repair 1. DNA-N-glycosylase removes the damaged base 2. AR endonuclease introduces a break in the DNA strand 3. Exonuclease removes a number of nucleotides 4. DNA polymerase fills the vacant site with complementary nucleotides 5. DNA ligase crosslinks the repaired DNA strand Error repair DNA replication by methylation Errors in the pairing of nitrogenous bases during DNA replication occur quite often (in bacteria once per 10 thousand nucleotides), as a result of which nucleotides that are not complementary to the nucleotides of the maternal chain are included in the daughter DNA chain - mismatches (English mismatch does not match). Despite the fact that prokaryotic DNA polymerase I has the ability to self-correct, its efforts to eliminate erroneously attached nucleotides are sometimes insufficient, and then some incorrect (non-complementary) pairs remain in the DNA. In this case, repair occurs using a specific system associated with DNA methylation. The action of this repair system is based on the fact that after replication, after a certain time (several minutes), DNA undergoes methylation. In E. coli, adenine is methylated mainly to form N6-methyl-adenine (N6-mA).

10 Up to this point, the newly synthesized (daughter) strand remains unmethylated. If there are unpaired nucleotides in such a chain, then it undergoes repair: Thus, methylation labels DNA and turns on the replication error correction system. In this repair system, special structures are recognized: the G-N6-mA-T-C sequence and the subsequent deformation in the double helix at the place of lack of complementarity (Fig. below). A rather complex complex of repair enzymes takes part in the elimination of unpaired nucleotides in a hemimethylated DNA molecule, which scans the surface of the DNA molecule, cuts out a section of the daughter chain that resorts to mismatches, and then creates conditions for building it up with the necessary (complementary) nucleotides. Various components of this complex have different nuclease, helicase, and ATPase activities, which are necessary for introducing breaks in DNA and cleaving nucleotides, unwinding the DNA double helix, and providing energy for the movement of the complex along the repaired part of the molecule. A complex of repair enzymes similar in structure and functions was also found in humans. Recombinant (post-replicative) repair 10 In cases where, for one reason or another, the above repair systems are disrupted, gaps (underrepaired areas) can form in DNA chains, sometimes of very significant sizes, which is fraught with disruption of the replication system and can lead to cell death . In this case, the cell is able to use for the repair of one DNA molecule another DNA molecule obtained after replication, i.e., to involve the recombination mechanism for this purpose. In bacteria In bacteria, the Rec A protein takes part in recombinant repair. It binds to a single-stranded DNA region and involves it in recombination with homologous regions of intact strands of another DNA molecule. As a result, both the broken (containing gaps) and intact strands of the DNA molecule being repaired turn out to be paired with intact strands.

11 complementary DNA regions, which opens up the possibility of repair by the above-described systems. In this case, a certain fragment can be cut out and a gap in the defective chain can be filled with it. The resulting gaps and breaks in the DNA chains are filled with the participation of DNA polymerase I and DNA ligase. SOS reparation The existence of this system was first postulated by M. Radman in 1974. He also gave the name to this mechanism by including the international distress signal "SOS" (save our souls) in it. Indeed, this system turns on when there is so much damage in the DNA that it threatens the life of the cell. In this case, the activity of a diverse group of genes involved in various cellular processes associated with DNA repair is induced. The inclusion of certain genes, determined by the amount of damage in DNA, leads to cellular responses of different significance (starting with the standard repair of damaged nucleotides and ending with the suppression of cell division). The most studied SOS-repair in E. coli, the main participants of which are proteins encoded by the Rec A and Lex A genes. coli, and the second one (the Lex A protein) is a transcription repressor of a large group of genes intended for bacterial DNA repair. When it is inhibited or resolved, reparation is activated. Binding of Rec A to Lex A leads to cleavage of the latter and, accordingly, activation of repair genes. In turn, the induction of the bacterial SOS system serves as a danger signal for the lambda phage and leads to the fact that the prophage switches from the passive to the active (lytic) way of existence, thereby causing the death of the host cell. The SOS repair system has been found not only in bacteria, but also in animals and humans. eleven

12 12 Genes involved in SOS repair of DNA damage Genes uvr A, B, C, D Rec A lex A rec N, ruv ssb umu C, D sul A Consequences of gene activation Repair of damage to the secondary structure of DNA Post-replicative repair, induction of the SOS system Switching off the SOS system Repairing double-strand breaks Ensuring recombination repair Mutagenesis caused by changes in the properties of DNA polymerase Suppression of cell division Conclusion Repair of DNA damage is closely related to other fundamental molecular genetic processes: replication, transcription, and recombination. All these processes turn out to be intertwined into a common system of interactions served by a large number of various proteins, many of which are polyfunctional molecules involved in the control of the implementation of genetic information in pro- and eukaryotic cells. At the same time, it is obvious that nature "does not skimp" on control elements, creating the most complex systems for correcting those damages in DNA that are dangerous for the organism and especially for its offspring. On the other hand, in those cases when the reparative capacity is not enough to maintain the genetic status of the organism, there is a need for programmed cell death apoptosis. Molecular Biology M. AKADEMA C.

13 SCHEME OF NUCLEOTIDE EXCISION REPAIR IN E.COLI WITH PARTICIPATION OF EXINUCLEASE 1. TRANSCRIPTIONLY INDEPENDENT MECHANISM 13

14 2. TRANSCRIPTION DEPENDENT MECHANISM 14

15 3. GENERAL STAGE OF REPAIR 15 LEGEND A - uvr protein A B - uvr protein C C - uvr protein C small black triangle sign indicates the location of damage

16 REPAIR SCHEME ASSOCIATED WITH DNA METHYLATION 16


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Genetic repair- the process of eliminating genetic damage and restoring the hereditary apparatus, which occurs in the cells of living organisms under the action of special enzymes. The ability of cells to repair genetic damage was first discovered in 1949 by the American geneticist A. Kelner. Subsequently, diverse mechanisms for the removal of damaged areas of hereditary material were investigated, and it was found that genetic repair is inherent in all living organisms. Apparently, the ability to repair genetic damage appeared at the early stages of the development of life on Earth and improved as the evolution of living beings: the most ancient representatives of the plant and animal world have repair enzymes. To date, a large number of specialized repair enzymes have been discovered, as well as genes (see Gene) that control their synthesis in cells. It has been proven that changes in these genes increase the body's sensitivity to adverse and damaging factors, contribute to an increase in hereditary changes - mutations (see Mutagenesis), the occurrence of diseases and premature aging. It has been established that some human hereditary diseases develop in connection with violations of the synthesis of repair enzymes. Two forms of genetic repair, photoreactivation and dark repair, have been studied in detail.

Photoreactivation, or light recovery, was discovered in 1949. A. Kellner, studying the biological effect of radiation in experiments on microscopic fungi and bacteria, found that cells exposed to the same dose of ultraviolet radiation survive much better if, after irradiation in the dark, they are placed in normal natural light conditions. Based on this, it was suggested that part of the damage to the genetic structures of cells that occur under the action of ultraviolet radiation occurs in the light.

It took almost two decades to decipher the effect of photoreactivation discovered by A. Kellner. It turned out that ultraviolet irradiation has the ability to disrupt the structure of deoxyribonucleic acid molecules (abbreviated as DNA - see Nucleic acids) that carry genetic information. The DNA molecule contains four types of so-called nitrogenous bases: adenine, guanine, cytosine and thymine - and consists of two strands twisted into a spiral. Often in the same thread, the same bases are located side by side. Under the action of ultraviolet irradiation, chemical bonds are broken in some of the nitrogenous bases, and if this happens, for example, in adjacent thymine bases, they combine with each other, forming the so-called thymine dimer. Thymine dimers sharply disrupt the structure of the DNA double helix, as a result of which the meaning of the genetic record changes, which leads either to hereditary defects that are passed on to descendants or to cell death. To "treat" these damages, some cells have special enzymes called photoreactivators. These enzymes are able to “recognize” areas in DNA damaged by ultraviolet irradiation, attach to them and destroy the bonds that have arisen between two thymines, restoring the original (normal) DNA structure. However, the "therapeutic effect" of photoreactivating enzymes - the splitting of linked sections of the DNA molecule and the restoration of its original normal structure - is manifested only with the participation of light energy. Then, from here, light plays the role of an activating factor in these processes, triggering the photoreactivation reaction. Until now, this remains the only example of biochemical reactions in which light energy acts as an activator.



Initially, the ability to photoreactivate was found in microorganisms; later, photoreactivating enzymes were found in the cells of some fish, birds, amphibians, insects, higher plants, and algae. For a long time, this type of repair could not be found in mammals and humans. Only in 1969 it was proved that the cells of marsupials have the ability to photoreactivate. This fact was explained by the peculiarities of the biology of these most ancient inhabitants of the Earth: it was believed that the presence of a photoreactivating enzyme in marsupials is of exceptional importance, since only in them (among other mammals) the embryo is exposed to sunlight (including ultraviolet radiation) in the process of transferring it in the mother's bag. Recent studies indicate the possibility of the presence of a photoreactivating enzyme in human skin cells; perhaps that is why massive ultraviolet irradiation, for example, during sunburn, does not cause damage to the human genetic apparatus.

Dark reparation, unlike photoreactivation, is universal. It eliminates various structural DNA damage resulting from a variety of radiation and chemical effects. The ability for dark repair has been found in all cellular systems and organisms. The ability of microorganism cells to repair genetic damage in the dark was discovered in 1955, but the details of this process began to be clarified only starting in 1964. It turned out that the mechanisms of dark repair are fundamentally different from the mechanism of photoreactivation. The first difference is that, while the photoreactivating enzyme cleaves sections of the DNA molecule linked by ultraviolet irradiation during the reaction in light, the damaged sections are removed from the DNA molecule during dark repair. The second difference is related to the number of "cured" damage. The photoreactivating enzyme is active against only one type of DNA damage - the formation of thymine dimers under the action of ultraviolet irradiation. Enzymes that carry out dark repair are able to eliminate various structural damage to DNA that appear as a result of various effects on cells - both chemical and radiation. As a result of dark repair, a kind of molecular “surgical” intervention is carried out: damaged areas are “cut out”, and the resulting “gaps” are filled in by local (local) synthesis or exchange of sections between damaged and undamaged DNA strands, as a result of which its original normal structure is restored. Dark repair is carried out under the control of a large number of enzymes, each of which is responsible for a certain stage of this complex process. Two types of dark repair, excisional and post-replicative, have been studied in detail. During excisional repair, the damaged section of DNA is cut out and replaced before the start of the next cycle of cell reproduction, more precisely, before the start of duplication (replication) of DNA molecules. The biological meaning of this process is to prevent the fixation of hereditary changes (mutations) in the offspring and the subsequent reproduction of the changed forms. Excision repair is the most economical and efficient form of genetic repair. It has been established that during its normal functioning, up to 90% of existing genetic damage is removed from microorganisms before the start of DNA replication, and up to 70% from the cells of higher organisms. Excisional repair is carried out in several stages.

First, a special enzyme “cuts” one of the DNA strands, close to the damaged area, then the damaged area is removed completely, and the resulting “gap” is filled in by special enzymes (DNA polymerases), which supply the missing links, borrowing them from the undamaged thread. The ability for excisional repair has been established in cells of microorganisms, higher plants and animals, as well as in humans.

Post-replicative repair- the last opportunity for the cell to eliminate existing genetic damage, to protect offspring from changes in hereditary traits. If so many damages occur in the DNA that during the excision repair the cell does not have time to completely eliminate them, or if the genes that determine the possibility of excision repair are damaged, then in the process of reproduction (doubling, replication) of DNA in the daughter strands at the site of damage present in the maternal threads, "gaps" are formed. This is due to the fact that the enzyme responsible for DNA replication (the synthesis of a daughter strand on the parent DNA strand) cannot “read” the distorted information at the damaged point of the parent strand. Therefore, reaching the damaged site, which remained uncorrected during excisional repair, this enzyme stops, then slowly (at a speed hundreds of times slower than usual) passes through the damaged area and resumes normal synthesis of the daughter thread, retreating from this place. This happens at all points where the parent DNA strand remains damaged by the start of replication. Of course, if the number of damages is too great, replication stops completely and the cell dies. But the cell cannot exist for a long time with DNA molecules that carry gaps. Therefore, after replication, but before cell division, the process of post-replicative repair begins. Before cell division, two double-stranded DNA molecules are formed in it. If one of them carries damage at some point in one strand and a gap in the opposite strand, then in the other double-stranded DNA molecule, both strands at this point will be normal. In this case, an exchange of DNA sections can occur - recombination (see Gene, gene exchange): an intact section will be cut out from a normal DNA molecule and inserted into the place of the damaged section in another molecule, due to which the damaged genetic material will be replaced by normal. Following this, spec. enzymes (DNA polymerases) will repair the “gaps” (now they will be able to do this, since there will be no damage in both molecules at this site), the newly synthesized and old strands will be connected to each other, and the original DNA structure will be as a result this one is completely restored. In accordance with the nature of the process associated with the implementation of recombination, this type of post-replicative repair is also called recombination.

Apparently, the described mechanism is not the only way to restore the normal structure of DNA after its doubling (replication). In any case, a mechanism is known in which links are inserted into the gaps that do not correspond to the original structure of the DNA being repaired, i.e., mutations occur. It is possible that this happens in those cases when the cell, for one reason or another, cannot repair its DNA by any of the methods described above and it has the last chance - either to survive at the cost of mutations, or to die. The interaction of various repair systems, the regulation of their activity in the cell, and the exact operating time have not yet been sufficiently studied. It was found that in some cases, the coordinated action of excisional and post-replicative repair enzymes occurs in the cell. For example, if two strands of DNA are interconnected (crosslinked), which occurs under the action of many poisons (for example, the poisonous substance mustard gas), then the excisional repair enzyme starts the repair reaction first, cutting one strand of DNA, and then the post-replication repair enzymes come into action, completing the process.

Systems of postreplicative repair enzymes have been found in human cells. It has not yet been fully elucidated what are the exact enzymatic mechanisms that provide this type of repair in human cells, but it is known that recombination and random filling of gaps with the appearance of mutations can occur in human cells. The relative efficiency of known genetic repair processes is also not clear. It has been established, for example, that E. coli cells irradiated with ultraviolet light, under the condition of normal functioning of the excision repair system, are capable of removing up to 1000 damages from DNA. When more damage occurs in the DNA, the cell dies. If the system of excision repair is disabled, then only about 100 lesions can be removed due to post-replicative repair. If both repair systems are absent, the cell dies from the only damage occurring in the DNA.

reparation and mutation. After, in the first studies of genetic repair, a close relationship was established between the elimination of damaged areas and a decrease in the frequency of mutations. Later it was proved that disturbances in the activity of repair enzymes lead to a sharp increase in the number of mutations. At the same time, it has now been established that mutations can also appear in the course of the genetic repair processes themselves due to “mistakes” in the work of repair enzymes. Although the most accepted hypothesis is that repair processes are predominantly error-free and that only the reaction of post-replicative repair, during which random bases are built into the gap, causes mutations, an increasing amount of experimental data is accumulating, indicating that even a relatively small number of errors repair leads to the appearance of a significant number of mutations that are detected both under normal (natural) conditions and in the case of exposure to damaging factors.

Reparation at different stages of individual development of organisms. The ability to carry out one or another type of genetic reparations may change at different stages of development of organisms. Studies show that the maximum efficiency of all repair processes in mammals (including humans) is manifested at the time of embryonic (intrauterine) development and at the initial stages of body growth. For example, for a long time it was not possible to find an excisional repair reaction in rodents (hamster, rat, mouse, and others), and only recently it was found that this type of repair takes place at the embryonic stage of development and stops at later stages. It is often carried out only in dividing cells, for example, in the developing nerve cells of the embryo. If conditions are created under which the division of these cells is suppressed, then the repair of single-strand breaks in DNA, caused, for example, by X-ray irradiation, is also eliminated.

Reparation disorders and human diseases. In 1968, the English scientist D. Cleaver proved that a human hereditary disease is xeroderma pigmentosa, the signs of which are redness, the formation of growths, often with malignant degeneration of skin areas at the site of exposure to sunlight, as well as visual impairment, nervous system and others, due to a defect in the activity of excision repair enzymes. Later it was found that some more human hereditary diseases are caused by violations of genetic repair processes. These diseases include Hutchinson's syndrome, which develops dwarfism, premature aging and progressive dementia. Damage to the genes encoding repair enzymes is responsible for the emergence of a number of forms of such a relatively common disease as systemic lupus erythematosus and others.

The study of the molecular nature of these diseases gives reason to hope for a relatively rapid development of methods for their treatment. Success in this direction depends both on the study of the details of genetic repair processes and the study of the possibility of isolating actively working enzymes from normal organisms (especially microbes) with their subsequent introduction into the patient's body, and on methods of replacing diseased genes with healthy ones (see Genetic Engineering). While the second path so far remains only in the field of hypotheses, experimental work has begun in the first direction. Thus, Japanese researchers K. Tanaka, M. Bekguchi and I. Okada at the end of 1975 reported the successful use of one of the repair enzymes isolated from bacterial cells infected with a bacterial virus to eliminate a defect in cells taken from a patient suffering from xeroderma. In order for this enzyme to successfully enter human cells cultured under artificial conditions, a killed Sendai virus was used. However, to date, such studies have not been carried out on the human body. Another direction is associated with the development of methods for the early diagnosis of diseases caused by defects in repair enzymes.