DNA repair

General information

DNA damaging agents

Radiation

1. ionizing radiation (gamma rays, x-rays)

2. Ultraviolet radiation (especially ~260 nm, it is in this region that the maximum absorption of DNA occurs)

Reactive oxygen radicals produced during normal cellular respiration in various biochemical pathways.
Environmental chemicals.

many hydrocarbons.

Chemicals used in anticancer chemotherapy.

Types of DNA damage

1. All four bases in DNA (A, T, C, G) can be covalently modified at various positions.
The most common is the loss of the amino group (deamination) - in this case, C turns into U.
Incorrect base incorporation occurring due to errors in the work of DNA polymerases during replication.
Most often, uracil is included instead of thymine.
Structure violations.
Breaks can occur in DNA. Breaks can be single-stranded, or both DNA strands can break.

Ionizing radiation can be a common cause of such ruptures.
A covalent bond may be formed between adjacent bases, and the bond may be formed between adjacent bases in the same strand or between two strands of DNA.
types of DNA damage
one base change
apurinization
change from s to y
substitution of A for hypoxanthine
base alkylation
insertion or deletion of a nucleotide
embedding a similar base
change of two bases
thymine dimer formation
cross-linking with a bifunctional alkylating agent
chain breaking
ionizing radiation
radioactive destruction of core elements
cross links
between the bases of one thread or two parallel threads
between DNA and protein molecules, such as histones

Repair of damaged bases

Damaged bases can be fixed in various ways:
Direct chemical damage repair.

Excision repair (ER), in which the damaged base is removed and replaced with a new one. There are three excision repair models, each using its own set of enzymes.
Base excision repair (BER).
Nucleotide excision repair (NER).
Mismatch Reparation (MMR).

Direct damage repair.

The most common cause of point mutations in humans is the spontaneous addition of a methyl group, one type of alkylation. Such modifications are corrected by enzymes called glycosylases, which correct the error without destroying the DNA strand.

Some drugs used in chemotherapy also damage DNA by alkylation.
The problem of repair is that, with a limited set of enzymes and mechanisms, the cell must cope with many damages caused by a wide variety of chemical and physical agents.

Base excision repair (BER)

Main key events:

1. Removal of the damaged base (occurs ~20,000 times a day in every cell of the human body) DNA glycosylamine. Humans have at least 8 genes encoding various DNA glycosylases, each of which recognizes a different set of base damage.
2. Removal of deoxyribophosphate leads to the formation of a void in the DNA.
3. Replacement with the correct nucleotide. This function in humans is performed by betta DNA polymerase.
4. Ligation of the chain break. There are two enzymes, both require ATP.

Nucleotide excision repair (NER)

NER differs from BER in several ways.
Using various enzyme systems.
Even if the error is in one nucleotide, many nucleotides are removed at once in the area of ​​damage.

Main key events of NER:
1. Damage is recognized by one or more factors associated with the site of damage.
2. DNA unwinds at the site of damage. This process involves
various transcription factors IIH, TFIIH, (which also work in normal transcription).
3. The DNA cut occurs from the 3" and 5" ends of the damage, as a result of which the DNA fragment containing the damaged nucleotide is removed.
4. A new DNA strand is completed according to the template of an intact DNA strand by delta or epsilon polymerases.
5. Ligases crosslink the newly synthesized end of the chain.

Pigmentary xeroderma (XP)
XP is a rare hereditary human disease that causes damage to the skin when exposed to light, which ultimately leads to the development of skin cancer and death of the patient.
The disease occurs due to mutations in the genes involved in NER repair. For example:
XPA encodes a protein that binds to the injury site and assists in the assembly of the repair complex.
XPB and XPD, which are parts of the transcription factor TFIIH. Certain mutations in XPB and XPD may also be responsible for premature aging.
XPF cuts the DNA strand at the 5" end of the damage.

The XPG cuts the chain at the 3" end.

Mismatch Reparation(MMR)

Mismatch repair corrects erroneously embedded intact bases that do not form a normal Watson-Crick pairing (A T, C G). Such errors occur during the operation of DNA polymerase during replication.
Mismatch repair involves enzymes involved in both BER and NER repair, as well as specialized enzymes.
DNA synthesis during mismatch repair is carried out by DNA polymerases delta or epsilon.
The mismatch repair system is involved in increasing the accuracy of recombination during meiosis.

DNA break repair

Ionizing radiation and some chemicals can break one or two strands of DNA.
Single strand breaks (SSB)
Breaks in one of the DNA strands are often repaired by enzymes involved in BER repair.
Double strand breaks (DSB)
There are two mechanisms that are able to eliminate DNA double-strand breaks:
Direct connection of broken ends. This process requires special
enzymes that recognize and bind the broken ends with their subsequent stitching. If the broken DNA has blunt ends and the connection of two DNA fragments occurs by chance, then such a repair is called NHEJ. The Ku protein is essential for NHEJ. Ku is a heterodimeric subunit consisting of two proteins Ku70 and Ku80.
Errors that occur during direct attachment can be the cause of translocations.
Polynucleotide ligase- restored. single chain DNA breaks

Homologous recombination

Homologous recombination is able to repair broken ends of chromosomes using DNA from the intact sister chromatid available after chromosome duplication.
The genes required for homologous recombination are BRCA-1 and BRCA-2.

gene conversion
The donor of the new gene can be:
homologous chromosome (during meiosis)
sister chromatid (also during meiosis)
duplicated gene on the same chromosome (during mitosis)

Correction of errors due to 3'-5' exonuclease activity of polymerase during replication (only in prokaryotes) (mutation of E. coli mutD-mutator-change-DNA-pol.III subunit)
Thymine dimers, photolyase enzyme gene-phr (in lower eukaryotes)
Removal of attached alkyl and methyl groups - O-6-methylguanine transferase (ada gene) - removes O-6-methylguanine
excisional r. bases [E.coli] [man | damage recognition. XPA protein in association with RPA | involved f-r transkr. TFIIH (P52, P34, P44, P62, XPB-XPD-helicase activity) | ERCC1-XPF, XPG - nucleases, cut DNA on both sides of the damage. | DNA polymerase- and auxiliary. proteins RFC and PCNA fill the gap]
R. nitrogenous basics.-glycosylase removes basic.
AP site (apurinic, apyrimidine) | AP-endonuclease recognizes a gap, a cut. 5'-DNA
postreplicative r. (PRP)
SOS-r. proteins comp. with DNA polymerase, daughter. DNA builds up against damage. DNA

Abbreviations.
BER - Base Excision Repair

NER - Nucleotide Excision Repair
MMR - Mismatch Repair
NHEJ - Nonhomologous End-Joining

mismatch reparation

During replication, as a result of polymerase errors, non-complementary nucleotides can be inserted, which can lead to mutations in the daughter DNA strand. Unpaired bases are recognized by mismatch repair enzymes and carry out the replacement of mismatched nucleotides.

Enzymes of this system provide homologous recombination, as well as cell cycle delay in response to DNA damage.
The E. coli mismatch repair system, which uses MutHLS proteins, recognizes and repairs all non-complementary base pairs except C–C. In addition, this system repairs small inserts in one of the DNA strands resulting from replication errors, the length of which does not exceed four nucleotides.
Normally E. coli DNA is methylated Dam-methylase by sites GATC. However, after replication is completed, the daughter strand of DNA remains unmethylated for some time.
This system can be reconstructed in vitro using
DNA with a single methylated strand as a substrate, to which purified proteins MutH, MutL, MutS, UvrD (helicase II), DNA polymerase III holoenzyme, DNA ligase, SSB protein, and one of the exonucleases: ExoI, ExoVII or RecJ are added . The repair process is initiated by introducing a single-strand break in the unmethylated strand near the partially methylated GATC site, followed by hydrolysis of the DNA strand and filling in the resulting single-strand gap. In this case, the MutS protein binds to mismatched nucleotides. The MutL protein has no enzymatic activity, although it interacts with MutS and is necessary for the activation of MutH, an endonuclease that performs single-strand DNA breaks. Thus, the MutS–MutL complex assembled at the DNA region with the mismatched nucleotide stimulates the endonuclease (nickase) activity of MutH. The cell-free system does not require the presence of MutH in the presence of a single-strand break in the DNA substrate. MutHLS repair system can
use partially methylated GATC sequences located above and below the damaged DNA region. At the same time, in
excision of the erroneously inserted nucleotide, in addition to helicase II, one of the exonucleases takes part: ExoI (3'-exo), ExoVII (3'- and 5'-exo), or RecJ (5'-exo), depending on the location of the GATC site in relation to corrected nucleotide. Following excision of the nucleotide, the resulting single-stranded gap is filled with the DNA polymerase III holoenzyme in the presence of the SSB protein and DNA ligase. It should be emphasized that the use of the MutH protein and Dam methylase to recognize the daughter strand of replicated DNA is a unique property of Gram-negative bacteria. Gram-positive bacteria do not methylate DNA strands for labeling purposes. If the GATC sites are fully methylated, the E. coli MutHLS repair system modifies mismatched nucleotides in both DNA strands with equal efficiency.
E. coli has at least two more specific
Mismatched nucleotide repair pathways. The VSP (very short patchrepair pathway) system repairs non-complementary G–T pairs, replacing them with G–C. It is believed that such pairs are formed as a result of deamination of 5-methylcytosine at sites where C residues are methylated by Dcm-methylase. With lower efficiency, the same system replaces G–U pairs with G–C. Another MutY-dependent repair system specifically reverses the effects of oxidative damage to guanine. If dGTP is oxidized to form 8-oxo-dGTP, the MutT protein cleaves the latter, preventing it from being incorporated into DNA. If it nevertheless turns on opposite residue C, then Fpg glycosylase (MutM) removes this modified base. In the case when 8-oxo-G remains in the DNA, it pairs with A in the next round of replication, and as a result, the G–C>T–A transversion can occur. In this case, the MutY protein acts as a DNA glycosylase, removing the A residue from the incorrect pair, and as an AP lyase, introducing a single-stranded
break in the neighborhood of the AP site. The following are the processes already discussed above in connection with the functioning of the BER repair system. The sequence of reactions involving MutY also repairs non-complementary A–G and A–C pairs to form C–G and G–C pairs, respectively. Mismatched base repair in eukaryotes occurs when
participation of a complex of proteins similar to the MutHLS system of bacteria. The human GTBP protein is a homologue of the bacterial MutS protein, while in yeast, the Msh6 protein plays the corresponding role. The recognition of mismatched nucleotides in humans is carried out by the MSH2–GTBP heterodimer. MutL homologues in S. cerevisiae cells are MLH1 and PMS2 proteins, which also exist as heterodimeric complexes. Mutations in the genes encoding these proteins in humans are accompanied by the formation of a mutator phenotype and the development of hereditary nonpolyposis colon cancer (HNPCC syndrome).

Direct reparation

There are two main pathways for the repair of alkyl bases: base excision repair (BER) and direct repair of damaged bases. During BER, DNA glycosylases cleave cytotoxic alkylated bases in DNA at the first step with the formation of the AP site and its subsequent processing. In the case of direct repair, two methods are implemented: repair by alkyl transferases or oxidation of the alkyl group, in both cases, regeneration of intact bases occurs. If repair occurs by alkyltransferases (in mammals, only O 6 -alkylguanine is repaired along this path), then O 6 -alkylguanine transferase (AGT) transfers a methyl or ethyl group from O 6 -alkylguanine to one of its own cysteine ​​residues. The protein alkylated as a result of its own activity is inactivated, but can serve as a regulator of the activity of its own gene and several others. Unlike suicidal O 6 -methylguanine transferases, which demethylate the highly mutagenic and toxic
damage to O 6 -methylguanine, AlkB from E. coli and its human analogs hABH2 and hABH3 oxidizes 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) methyl groups in DNA to regenerate unmodified adenine and cytosine bases.

O 6 -alkylguanine transferase

O 6 -alkylguanine transferase activity is found in most organisms and prevents the mutagenic action of O 6 -alkylguanine. AGT converts O 6 -alkylguanine to guanine by transferring an alkyl group from DNA to a reactive cysteine ​​residue in the protein in an irreversible reaction.

This covalent attachment of an alkyl group to a cysteine ​​residue inactivates the enzyme. Therefore, AGT is a suicidal enzyme that undergoes proteolytic degradation after one
transalkylation reactions. Structural studies reveal that the AGT active site is located in the enzyme volume at some distance from the DNA-binding site. The enzyme is thought to "work" by a "nucleotide flip" mechanism to bring the substrate base close to the nucleophilic active site of AGT.

The importance of AGT in protecting mammals from the toxic and mutagenic effects of alkylating agents has been demonstrated in mice. Transgenic mice overexpressing AGT exhibit significantly lower levels of tumorigenesis in response to the action of the methylating agent, N-methyl-N-nitrosourea, while AGT-deficient mice were much more susceptible to tumor initiation and the toxic effects of this agent. compared to wild mice. AGT is an important enzyme in antitumor therapy as it interferes with the cytotoxic effects of antitumor agents of the chloroethylnitrosourea (CENU) class, e.g.
BCNU (N,N-bis(2-chloroethyl)N-nitrosourea) or temozolomide. It has been shown that the amount in which AGT is present in tumors mainly determines how favorable the outcome of antitumor therapy using CENU will be. CENU initially reacts with the O 6 carbonyl group of guanine to form the compound 4 , which is subsequently converted to N 1, O 6 -ethanoguanine 5 . Compound 5 regroups within a few hours into a physiologically active ICL 6 . AGT interferes with education 6 when interacting with 4 or 5 , renewing guanine or forming a DNA-protein adduct 8 . Experimental confirmation of the formation of the adduct 8 , but it was isolated in too small an amount for its detailed description. In a biochemical study of this problem, N 1, O 6 -ethanoxanthin was introduced
9 as a stable analogue 5 in DNA. Ethanoxanthin 9 reacts with AGT to form a stable DNA-protein adduct 7 . This approach allowed the formation of a covalently bound AGT-DNA adduct 10 in large quantities, which can be used to determine the structure of AGT associated with DNA. The interaction of AGT and alkylation therapy has led to the search for AGT inhibitors that can be used in cancer therapy in conjunction with alkylating agents. To date, inhibitors have been created, mainly guanine derivatives with substituents in the O 6 position. O 6 -benzylguanine 2 was found to be a typical AGT inhibitor against which new molecules are being compared. The effectiveness of O 6 -BzG in enhancing CENU cytotoxicity has been demonstrated in animal models. The limiting factor of this therapeutic approach is toxicity to healthy organs, partly to the bone marrow. Some
A group of scientists aims to circumvent this problem by generating an ATG variant that is resistant to O 6 -BzG inhibition, which can be used to protect the bone marrow through gene transfer.

AlkB, hABH2 and hABH3 oxidoreductases

Another way of direct repair of alkyl bases is the oxidation of the alkyl group with the regeneration of the intact nitrogenous base. Escherichia coli's AlkB enzyme and two human analogs, hABH2 and hABH3, demethylate 1-methyladenine and 3-methylcytosine in DNA in a targeted manner. But unlike AGT, these enzymes have substrate specificity directed to the surface of the G:C and A:T base pairs. Damage to 1-alkyladenine
and 3-methylcytosine are formed when adenine and cytosine are in a single strand structure (during replication or transcription) and are substrates for AlkB, hABH2 and hABH3. They oxidize the methyl groups of 1-methyladenine (1-meA) and 3-methylcytosine (3-meC) in DNA to regenerate the nitrogenous bases of adenine and cytosine. It has also been shown that AlkB protects against toxic damage - an adduct with an ethyl group and converts 1-ethyladenine to adenine in DNA, which produces acetaldehyde as a result of the reaction. In this way, damage to the known mutagen and carcinogen ethylene oxide, which is endogenously formed during the metabolism of ethylene, and is also widely used as a fumigant for sterilization, is repaired. Hydroxyethyl adducts generated by ethylene oxide are found in cell DNA. Other small alkylating epoxides are also used in large quantities in the chemical industry. AlkB has been shown to reduce the toxic effects of DNA damaging agents that generate hydroxyethyl,
propyl and hydroxypropyl adducts. AlkB repairs alkylated 1-me-dATP triphosphates actively but inefficiently. It was assumed that this ability may reduce the level of incorporation of alkyl triphosphates during DNA synthesis; in addition, the Klenow fragment of DNA polymerase I in E. coli can use 1-me-dATP as a precursor for in vitro DNA synthesis. The human enzymes hABH2 and hABH3 also demethylated 1-methyladenine residues in poly(dA) and were ineffective on short substrates. Thus, hABH3 had very low activity on the d(Tp1-meApT) trimer, while no activity was found on hABH2.

AlkB and its human analogs are part of the α-ketoglutarate/Fe(II)-dependent superfamily of dioxygenases, and during the repair process, decarboxylation of β-ketoglutarate and oxidative demethylation of the damaged base occur together. 1-meA and 3-meC lesions are formed mainly in single-stranded DNA and presumably
occur at the replication fork and in actively transcribed genes where they can block DNA and RNA polymerases. Indeed, AlkB, hABH2, and hABH3 repair these lesions in single-stranded DNA, but oligonucleotides annealed to complementary strand after alkylation also repair. AlkB 1-methyladenine repair efficiency does not depend on the polynucleotide structure, but the presence of a nucleotide-5'-phosphate group is required. Also, the human enzymes hABH2 and hABH3 demethylated 1-methyladenine residues to poly(dA), they were ineffective on short substrates. In addition positively charged lesions (ribonucleosides 1-meA and 3-meC, respectively, pKa = 9.3 and 9.6) were better repaired than uncharged bases (1-meG and 3-meT). degree 3-meT) were repaired by AlkB, then the formal positive charge of the base is not a necessary condition for the functioning of AlkB.
it is not yet clear whether this result depends on positively charged bases being better recognized through electrostatic interactions with AlkB, or whether positively charged bases simply make DNA a better leaving group after methyl group hydroxylation.

Abbreviations:

• AGT - alkylguanine transferase
• BER - base excision repair
• DNA - deoxyribonucleic acid
• RNA - ribonucleic acid
• BCNU - N,N-bis(2-chloroethyl)N-nitrosourea
• CENU - chloroethylnitrosourea
• O 6 -BzG - O 6 -benzylguanine
• 1-meA - 1-methyladenine
• 1-meG - 1-methylguanine
• 3-meC - 3-methylcytosine
• 3-meT - 3-methylthymine

Literature:

» Orlando D. Scharer (2003) Angew. Chem. Int. Ed. 42, 2946-2974
» James C. Delaney and John M. Essigmann Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli
» Pertti Koivisto, Tod Duncan, Tomas Lindahl, and Barbara Sedgwick Minimal Methylated Substrate and Extended Substrate Range of Escherichia coli AlkB Protein, a 1-Methyladenine-DNA Dioxygenase*
» Duncan, T., Trewick, S. C., Koivisto, P., Bates, P. A., Lindahl, T. & Sedgwick, B. (2002) Proc. Natl. Acad. sci. USA 99, 16660-16665. 5. Aas, P. A., Otterlei, M., Falnes, P. O., Vagbo, C. B., Skorpen, F., Akbari, M., Sundheim, O., Bjoras, M., Slupphaug, G., Seeberg, E., et al. (2003) Nature 421, 859-863.
» Hollis, T., Lau, A., and Ellenberger, T. (2000) Mutat. Res. 460, 201-210
» Daniels, D. S., and Tainer, J. A. (2000) Mutat. Res. 460, 151-163
» Trewick, S. C., Henshaw, T. F., Hausinger, R. P., Lindahl, T., and Sedgwick, B. (2002) Nature 419, 174-178
» Falnes, P. O., Johansen, R. F., and Seeberg, E. (2002) Nature 419, 178-181
» Duncan, T., Trewick, S. C., Koivisto, P., Bates, P. A., Lindahl, T., and Sedgwick, B. (2002) Proc. Natl. Acad. sci. U. S. A. 99, 16660-16665
» Aas, P. A., Otterlei, M., Falnes, P. O., Vagbo, C. B., Skorpen, F., Akbari, M., Sundheim, O., Bjoras, M., Slupphaug, G., Seeberg, E., and Krokan , H. E. (2003) Nature 421, 859-863
» Aravind, L., and Koonin, E. V. (2001) Genome Biology 2, 0007.1-0007.8
» Bodell, W. J., and Singer, B. (1979) Biochemistry 18, 2860-2863
» Boiteux, S., and Laval, J. (1982) Biochimie (Paris) 64, 637-641
» Larson, K., Sahm, J., Shenkar, R., and Strauss, B. (1985) Mutat. Res. 150, 77-84
» Dinglay, S., Trewick, S. C., Lindahl, T., and Sedgwick, B. (2000) Genes Dev. 14, 2097-2105

DNA break repair

Photoreactivation

The absorption of UV radiation energy by DNA molecules leads to the formation of various types of damage. Although single- and double-strand breaks, as well as DNA-protein cross-links, can occur, the majority of UV-induced damage is due to the modification of nitrogenous bases, with the formation of cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone photoproducts (6-4PP), as the most common types of photodamage.

Pyrimidine dimers are inhibitors of both replication and transcription, which retards growth and leads to mutagenesis during DNA replication if such damage remains unrepaired.

Enzymes that specifically bind to CPD (CPD photolyase) or 6-4PP (6-4PP photolyase) and repair these damages are used to repair light-induced DNA damage in many organisms. CPD photolyases have been found in bacteria, fungi, plants, invertebrates and many vertebrates, 6-4PP photolyases have been found so far only in Drosophila, silkworm, Xenopus laevis and rattlesnakes, but not in Escherichia coli or yeast. Photolyase has not been found in humans. Photolyases contain FAD as a catalytic cofactor and an additional chromophore as a light harvesting antenna.

Additional chromophores are either 5,10-methenyltetrahydrofolate (MTHF) or 8-hydroxy-5-deazoriboflavin (8-HDF), with absorption maxima at 380 and 440 nm, respectively. The crystal structures of the E. coli and Anacystis nidulans CPD photolyases confirm that the enzymes rotate the pyrimidine dimer from the duplex to the well containing the catalytic cofactor to bind to DNA. The cyclobutane ring is then cleaved by electron light-induced transfer. CPD photolyases selectively recognize CPD, similar to DNA-binding proteins. White light or UV-B radiation induces the expression of CPD photolyases. Unlike CPD photolyases, 6-4PP photolyase is stably expressed and is not regulated by either white light or UV-B radiation.

Schematic representation of photoreactivation in chromatin. Giton octamers are blue, DNA is black. Photolyase binds to cyclobutane-pyrimidine dimers (CPD), rotates the pyrimidine dimer, and regenerates native pyrimidines in a light-dependent reaction. Photolyase preferentially repairs CPD in linket DNA. Repair in nucleosomes is slowed down and presumably facilitated by the dynamic properties of nucleosomes that move DNA damage to the linker DNA region.

The class of CDP-specific photolyases from microorganisms, defined as class I photolyases, was the first member of the photolyase family to be characterized. A closely related class of photolyases specific to 6-4-photoproducts has been discovered recently, members of this family have been found in Drosophila melanogaster, Xenopus laevis, and Arabidopsis thaliana. Cryptochromes, which are photoreceptors for the violet part of the light spectrum found in plants and other organisms, are also closely related to class I photolyases.

A more distantly related family of CPD photolyases, termed class II photolyases, has been identified in a number of species including animals, Archaebacterium, Eubacterium and higher plants. All of the characterized photolyases have been shown to contain reduced FAD and most contain secondary chromophores, depending on the species, either MTHF or 8-HDF. A similar reaction mechanism has been proposed for both classes of CPD photolyases. The MTHF or 8-HDF chromophore is like an antenna that absorbs violet light and uses the absorbed energy to regenerate FADH-.

The composition of the plant photolyase cofactor is not fully understood, although it has recently been shown that CPD photolyases from Arabidopsis containing only FADH had enzymatic activity.

Literature:

» Fritz Thoma, Light and dark in chromatin repair: repair of UV-induced DNA lesions by photolyase and nucleotide excision repair, Institut fur Zellbiologie, ETH-Zurich, Honggerberg, CH-8093 Zurich, Switzerland
» Characterization of Arabidopsis photolyase enzymes and analysis of their role in protection from ultraviolet-B radiation, Wanda M. Waterworth 1, Qing Jiang, Christopher E. West, M. Nikaido and Clifford M. Bray

Discovery history

Single-strand and double-strand DNA damage

The study of repair was initiated by the work of A. Kellner (USA), who discovered the phenomenon of photoreactivation (PR) - a decrease in damage to biological objects caused by ultraviolet (UV) rays, with subsequent exposure to bright visible light ( light repair).

Excision repair

Post-replicative repair has been discovered in cells E.Coli unable to cleave thymine dimers. This is the only type of repair that does not have a damage recognition step.

Notes

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Damaged during normal DNA biosynthesis in the cell or as a result of exposure to physical or chemical reagents. It is carried out by special enzyme systems of the cell. A number of hereditary diseases (eg, xeroderma pigmentosum) are associated with impaired repair systems.

Discovery history

The beginning of the study of repair was laid by the work of Albert Kellner (USA), who in 1948 discovered the phenomenon of photoreactivation - a decrease in damage to biological objects caused by ultraviolet (UV) rays, with subsequent exposure to bright visible light ( light repair).

R. Setlow, K. Rupert (USA) and others soon established that photoreactivation is a photochemical process that occurs with the participation of a special enzyme and leads to the cleavage of thymine dimers formed in DNA upon absorption of a UV quantum.

Later, when studying the genetic control of bacterial sensitivity to UV light and ionizing radiation, it was discovered dark repair- the property of cells to eliminate damage in DNA without the participation of visible light. The mechanism of dark repair of bacterial cells irradiated with UV light was predicted by A. P. Howard-Flanders and experimentally confirmed in 1964 by F. Hanawalt and D. Petitjohn (USA). It was shown that in bacteria after irradiation, damaged DNA sections with altered nucleotides are excised and DNA is resynthesised in the resulting gaps.

Repair systems exist not only in microorganisms, but also in animal and human cells, in which they are studied in tissue cultures. A hereditary disease of a person is known - xeroderma pigmentosa, in which repair is disturbed.

Sources of DNA damage

Main types of DNA damage

The device of the reparation system

Each of the reparation systems includes the following components:

• DNA helicase - an enzyme that "recognizes" chemically altered sections in the chain and breaks the chain near the damage;
• DNase (deoxyribonuclease) - an enzyme that "cuts" 1 DNA chain (a sequence of nucleotides) along a phosphodiester bond and removes a damaged area: exonuclease works on terminal nucleotides 3` or 5`, endonuclease works on nucleotides other than terminal ones;
• DNA polymerase - an enzyme that synthesizes the corresponding section of the DNA chain to replace the deleted one;
• DNA ligase is an enzyme that closes the last bond in the polymer chain and thereby restores its continuity.

Types of reparation

Direct reparation

Direct repair is the simplest way to eliminate damage in DNA, which usually involves specific enzymes that can quickly (usually in one stage) eliminate the corresponding damage, restoring the original nucleotide structure. This is how, for example, O6-methylguanine-DNA methyltransferase acts, which removes the methyl group from the nitrogenous base to one of its own cysteine ​​residues.

Excision repair

Excisional repair (English excision - cutting) includes the removal of damaged nitrogenous bases from DNA and the subsequent restoration of the normal structure of the molecule along the complementary chain. The enzyme system removes a short single-strand sequence of double-stranded DNA containing mismatched or damaged bases and replaces them by synthesizing a sequence that is complementary to the remaining strand.

Excision repair is the most common method for repairing modified DNA bases. It is based on the recognition of a modified base by various glycosylases that cleave the N-glycosidic bond of this base with the sugar-phosphate backbone of the DNA molecule. At the same time, there are glycosylases that specifically recognize the presence in DNA of certain modified bases (oxymethyluracil, hypoxanthine, 5-methyluracil, 3-methyladenine, 7-methylguanine, etc.). For many glycosylases, polymorphism associated with the replacement of one of the nucleotides in the coding sequence of the gene has been described to date. For a number of isoforms of these enzymes, an association with an increased risk of oncological diseases has been established [Chen, 2003].

The high stability of DNA is ensured not only by the conservatism of its structure and the high accuracy of replication, but also by the presence of special systems in the cells of all living organisms. reparations that remove damage from DNA.

The action of various chemicals, ionizing radiation and ultraviolet radiation can cause the following damage to the DNA structure:

damage to single bases (deamination leading to the conversion of cytosine to uracil, adenine to hypoxanthine; base alkylation; inclusion of base analogues, insertions and deletions of nucleotides);

base pair damage (formation of thymine dimers);

chain breaks (single and double);

the formation of cross-links between bases, as well as DNA-protein cross-links.

Some of these violations may also occur spontaneously, i.e. without the involvement of any damaging factors.

Any type of damage leads to a violation of the secondary structure of DNA, which is the cause of partial or complete blocking of replication. Such conformational disturbances serve as a target for repair systems. The process of restoring the DNA structure is based on the fact that genetic information is represented in DNA by two copies - one in each of the chains of the double helix. Due to this, damage in one of the chains can be removed by the repair enzyme, and this section of the chain is resynthesized in its normal form due to the information contained in the undamaged chain.

Currently, three main mechanisms of DNA repair have been identified: photoreactivation, excision, and post-replication repair. The last two types are also called dark reparation.

Photoreactivation is broken down by an enzyme photolyase, activated by visible light, thymine dimers that occur in DNA under the action of ultraviolet radiation.

excisional repair consists in recognition of DNA damage, excision of the damaged area, resynthesis of DNA according to the template of the intact chain with restoration of DNA chain continuity. This method is also called reparation by the type of splitting - substitution, or more figuratively, the "cut - patch" mechanism. Excisional repair is a multi-stage process and consists of:

1) "recognition" of damage;

2) incision of one DNA strand near the damage (incision);

3) removal of the damaged area (excision);

4) DNA resynthesis at the site of the removed site;

5) restoration of the continuity of the repaired chain due to the formation of phosphodiester bonds between nucleotides
(Figure 6.2)

Rice. 6.2 Excision repair scheme

Reparation begins with joining DNA-N-glycosylase to the damaged base. There are many DNA-N-glycosylases specific to various modified bases. Enzymes hydrolytically cleave the N-glycosidic bond between the altered base and deoxyribose, which leads to the formation of an AP (apurinic-apyrimidine) site in the DNA chain (first step). AP site repair can only occur with the participation of DNA insertases, which adds a base to deoxyribose in accordance with the rule of complementarity. In this case, there is no need to cut the DNA strand, cut out the wrong nucleotide and repair the break. With more complex damage to the DNA structure, the participation of the entire complex of enzymes involved in repair is necessary (Fig. 6.2.): AP-endonuclease recognizes the AP site and cuts the DNA chain near it (stage II). As soon as a break occurs in the circuit, the work comes into play AP exonuclease, which removes a DNA fragment containing an error (stage III). DNA polymerase b builds up the gap that has arisen according to the principle of complementarity (stage IV). DNA ligase connects the 3¢-end of the newly synthesized fragment with the main chain and completes the damage repair (stage V).

Postreplicative repair is switched on in those cases when the excisional one cannot cope with the elimination of all DNA damage before its replication. In this case, the reproduction of damaged molecules leads to the appearance of DNA with single-strand gaps, and the native structure is restored during recombination.

Congenital defects in the repair system are the cause of such hereditary diseases as xeroderma pigmentosum, ataxia-telangiectasia, trichothiodystrophy, and progeria.

DNA REPAIR

Reparation systems

2 Excision repair. Examples and types

3 Repair of DNA replication errors

4 Recombinant (post-replicative) repair in bacteria

5 SOS reparation

DNA repair systems are quite conservative in evolution from bacteria to humans and are best studied in E. coli.

There are two types of reparation:straight and excisional

Direct reparation

Direct repair is the simplest way to eliminate damage in DNA, which usually involves specific enzymes that can quickly (usually in one stage) eliminate the corresponding damage, restoring the original structure of nucleotides.

1. This works, for example,O6-methylguanine-DNA-methyltransferase

(a suicidal enzyme) that removes a methyl group from a nitrogenous base to one of its own cysteine ​​residues

In E. coli, up to 100 molecules of this protein can be synthesized in 1 minute. 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. DNA insertases

photolyase

3. Thymine dimers are "embroidered" by direct reparation starringphotolyase, which carry out the corresponding photochemical transformation. DNA photolyases are a group of light-activated enzymes with a wavelength of 300 - 600 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. E. coli photolyase is a 35 kDa protein tightly bound to oligoribonucleotide 10-15 nucleotides long required for enzyme activity.

Examples of direct reparation

1. Methylated base O 6-mG dimethylated by the enzyme methyltransferaseO6-methylguanine-DNA-methyltransferase (a suicidal enzyme) that transfers a methyl group to one of its residues

cysteine

2. AP sites can be repaired by direct insertion of purines with the help of enzymes calledDNA insertases(from English insert- insert).

SCHEME OF AN EXAMPLE OF DIRECT DAMAGE REPAIR IN DNA - Methylated Base O6- mgdemethylated by the enzyme methyltransferase, which transfers a methyl group to one of its cysteine ​​amino acid residues.

3. Photolyase attaches to the thymine dimer, and after irradiation of this complex with visible light (300-600 nm), the dimer expands

SCHEME OF EXAMPLE OF DIRECT REPAIR OF DAMAGE IN DNA – Photolyase

attaches to the thymine dimer and, after irradiation with visible light, this dimer expands

Excision repair

(from English excision - cutting).

DEFINITION

Excision repair includes removal damaged nitrogenous bases from DNA and subsequent recovery normal molecular structure.

MECHANISM

Several enzymes are usually involved in excision repair, and the process itself affects

not only damaged ,

but also adjacent nucleotides .

CONDITIONS

For excision repair, a second (complementary) strand of DNA is required. The general simplified scheme of excisional repair is shown in fig. 171.

STAGES

The first step in excision repair is excision of the abnormal nitrogenous bases. It's catalyzed by a groupDNA-N-glycosylase- enzymes that cleave the glycosidic bond between deoxyribose and a nitrogenous base.

IMPORTANT NOTE:

AthumanDNA-N-glycosylasehave a high substrate specificity: different enzymes of this family recognize and excise various anomalous bases(8-oxoguanine, uracil, methylpurines, etc.).

AtbacteriaDNA-N-glycosylasedoes not have such substrate specificity.

GENERAL EXCISION REPAIR ENZYMES

NAME	FUNCTION	MECHANISM
DNA-N-glycosylase	excision of abnormal nitrogenous bases	cleaves the glycosidic bond between deoxyribose and nitrogenous base
AP endonuclease	creates conditions for the work of the next enzyme - exonucleases	breaks the sugar-phosphate backbone of the DNA molecule in the AP site
exonuclease	cleaves a few nucleotides	sequentially cleaves several nucleotides from the damaged section of one DNA strand

SPECIFIC SEQUENTIAL STEPS OF THIS MECHANISE:

As a result of action DNA- N-glycosylasean AP site is formed, which is attacked by the enzyme AR-endonuclease. It breaks the sugar-phosphate backbone of the DNA molecule in the AP site and thereby creates the conditions for the work of the next enzyme - exonucleases, which sequentially cleaves off several nucleotides from the damaged section of one DNA strand.

In bacterial cells the vacated space is filled with the corresponding nucleotides with the participation DNA polymerase I oriented to the second (complementary) strand of DNA.

Because DNA polymerase I is able to extend the 3' end of one of the strands at a break in double-stranded DNA and remove nucleotides from the 5' end of the same break,

those. realize “nick-broadcast” , this enzyme plays a key role in DNA repair. The final stitching of the repaired areas is carried out DNA ligase.

In eukaryotic (mammalian) cells

DNA excision repair in mammalian cells is accompanied by a sharp surge in the activity of another enzyme,poly ADP-ribose polymerase . At the same time, it happens ADP-ribosylation of chromatin proteins(histones and non-histone proteins), which leads to a weakening of their connection with DNA and opens access to repair enzymes.

Donor ADP-ribosein these reactionsNAD+, whose reserves are greatly depleted during excisional repair of damage caused by X-ray irradiation:

Negatively charged residues ADP-ribose from the internal composition of the molecule NAD+ join via a radicalglutamine acids or phosphoserineto chromatin proteins, which leads to the neutralization of the positive charges of these proteins and the weakening of their contact with DNA.

WHAT IS A GROUP OF ENZYMES

DNA - glycosylases

cleaves the glycosidic bond between deoxyribose and a nitrogenous base

which leads to excision of abnormal nitrogenous bases

DNA - glycosylases , involved in the elimination of oxidative damage to DNA in cells prokaryotes and eukaryotes, are very diverse and differ in substrate specificity, spatial structure, and modes of interaction with DNA.

The most studied DNA glycosylases include:

endonuclease III(EndoIII),

forms amido pyrimidine-DNA-glycosylase (fpg)

Mut T And

Mut Ycoli.

Endonuclease IIIE. coli recognizes and specifically cleaves from DNA oxidized pyrimidine bases.

This enzyme is a monomeric globular protein consisting of 211 amino acids residues (mol. weight 23.4 kDa). The gene encoding Endo III has been sequenced and its nucleotide sequence has been established. Endo III is iron-sulfur protein [(4 Fe-4S )2+-protein], which has the element suprasecondary structure type "Greek key" (spiral - hairpin - spiral), serving to bind to DNA. Enzymes with similar substrate specificity and similar amino acid sequences have also been isolated from bovine and human cells.

Form amido pyridine-DNA-glycosylase E. coli "recognizes" and cleaves oxidized heterocyclic bases of the purine series .

EXCISION REPAIR SCHEME STAGE 1

DNAN

EXCISION REPAIR SCHEME

1 DNANglycosidase removes the damaged base

AR endonuclease introduces a break in DNA

2 Exonuclease removes a number of nucleotides

3 DNA polymerase fills the vacant site with complementary

Mononucleotides

DNA ligase crosslinks the repaired DNA strand

Mut T- a small protein with a molecular weight of 15 kDa, which has nucleoside triphosphatase activity, which is predominantly hydrolyses dGTP to dGMP and pyrophosphate.

Biological role of Mut T is to prevent the formation of non-canonical pairs during replicationA:G And A: 8-oxo-G.

Such pairs can appear when oxidized form

dGTP (8-oxo-dGTP) becomes substrate DNA polymerase.

Mut T hydrolyzes 8-oxo-dGTP10 times faster than dGTP.

It does 8-oxo-dGTPmost preferred substrateMutTand explains its functional role.

Mut Yis a specific adenine-DNA glycosylase that cleaves the N-glycosidic bond between adenine and deoxyribose adenosine, forming a non-canonical pair with guanine.

The functional role of this enzyme is to prevent mutation

T:A - G:A by cleavage of intact residue adeninefrom base pair A: 8-oxo-G.

Nucleotide excision repair

(ATP-dependent DNA damage removal mechanism)

Recently, in excision repair, special attention has been paid to the ATP-dependent mechanism for removing damage from DNA. This type of excision repair is called nucleotide excision repair (NER).

It includes TWO STAGES :

1. removal from DNAoligonucleotide fragments containing damage, and

Excinuclease

2. subsequent reconstruction of the DNA chain with the participation of a complex of enzymes (nucleases, DNA polymerases, DNA ligases, 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 from prokaryotes

So, in E. coli, B. subtilus, Micrococcus luteus, a fragment of length 12-13 nucleotides

Removal of a DNA fragment from eukaryotes

and in yeast, amphibians and humans, a fragment consisting of 24-32 nucleotides.

Excinucleasean enzyme that removes DNA fragments

DNA fragment is cleaved by an enzymeexcinuclease(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. The name of these proteins is given by the first letters of the words"ultra violet repair".

Protomer uvr Ahas ATPase activity, binds to DNA in the form of a dimer, carrying out

primary damage recognition and

bindinguvr B

Protomer uvr B has:

1 . Latent ATPase and latent helicase activity necessary to change conformations and unwind the DNA double helix;

2. Endonuclease activity, cleaving the internucleotide (phosphodiester) bond from the sideZ"-endcleaved fragment.

Protomer uvr Cacts like endonuclease, introducing a break in the repaired DNA strand with5"-endcut fragment.

So the protomersuvr A, uvr B, uvr Cinteract with DNA in a certain sequence, carrying out an ATP-dependent reactioncleavage of the 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. The model of excisional repair with the participation of the above enzymes is shown in fig. 172.

Excisional repairs in humans

Human excision repairs are also ATP dependent and includethree main stages :

damage recognition,

double cutting of the DNA strand,

reductive synthesis and

ligation of the repaired strand.

However, human DNA excision repair involves

25 different polypeptides ,

16 of which are involved in the cleavage of the oligonucleotide fragment, being protomersexcinucleases,

and the rest 9 carry out the synthesis of the repaired portion of the molecule.

In the DNA repair system in humans, a very significant role is played by transcription proteins -

RNA polymerase II And

TF Monone of the six major transcription factors eukaryote.

It should be noted that excision 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,

homology of chains of transcribed DNA regions,

chain damage effect and its effect on RNA polymerase.

IMPORTANT NOTE:

CODING CHAIN ​​DNA (chain of information storage)

MATRIX CHAIN ​​of DNA (information is written off from it)

It is known that such large damages as thymine dimer formation, block transcription in both bacteria and humans if they occur on matrix circuit DNA (damage to coding chains do not affect to the transcription complex). RNA polymerase stops at the site of DNA damage and blocks the work of the transcription complex.

Transcription-repair linkage factor (TRCF) .

In E. coli, the enhancement of transcriptional repair is mediated by one special protein -transcription-repair linkage factor (TRCF) .

This protein contributes :

1. detaching RNA polymerase from DNA

2. simultaneously stimulates the formation of a protein complex,

Carrying out the repair of 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 damaged base

2. AR-endonuclease introduces a break in the DNA chain

3. Exonuclease removes a number of nucleotides

4. DNA polymerase fills in the vacated area

Complementary nucleotides

5. DNA ligase cross-links the repaired DNA strand

Repair of DNA replication errors

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 whichinto the daughter strand of DNA nucleotides that are not complementary to the nucleotides of the maternal chain are included -mismatches(English mismatch n e match).

AlthoughDNA polymerase Ithe prokaryote has the ability to self-correct, its efforts to eliminate erroneously attached nucleotides sometimes not enough, and then some wrong (non-complementary) pairs remain in the DNA.

In this case, reparation occurs using a specific system associated withDNA methylation . The action of this repair system is based on the fact that after replication, after a certain time (several minutes), DNA undergoes methylation.

E. coli methylated mostly adenine with education

N6-methyl-adenine (N6-mA).

Up to this point, the newly synthesized(subsidiary)the chain remains unmethylated.

If there are unpaired nucleotides in such a chain, then it undergoes repair: Thusmethylation marks DNA and

includes error correction system replication.

In this reparation system, special structures are recognized:

subsequenceG-N6-mA-T-CAnd next behind it deformation

in the double helix at the site of lack of complementarity (Figure below).

in the elimination of unpaired nucleotides in semi-methylated a rather complex complex of repair enzymes takes part in the DNA molecule, which scans the surface of the DNA molecule,cuts a section of the child chain resorting to mismatcham, and then creates conditions for building up

its desired (complementary) nucleotides.

Different components of this complex have different activities.nuclease,

helicase,

ATPaznoy,

necessary to introduce breaks in DNA and cleave nucleotides, unwind the DNA double helix and provide 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

In those cases when, for one reason or another, the above repair systems are disrupted, gaps (underrepaired areas) can form in DNA chains, which have sometimes quite significant, 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 for this purpose the mechanismrecombination.

In bacteria

In bacteria, recombinant repair takes partRec A protein. It binds to a single-stranded DNA region and involves it in recombination withhomologous regions of intact strands of another DNA molecule .

As a result, both the broken (containing gaps) and intact chains of the DNA molecule being repaired turn out to be paired with intact complementary DNA regions, which opens up the possibility of repair by the above-described systems.

At the same time, there may be cutting specific fragment and

fillingwith its help gaps in the defective chain.

The resulting gaps and breaks in the DNA chains are filled with the participation ofDNA 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 in it the international distress signal "SOS" (save our souls).

Indeed, this system turns on when damage to the DNA becomes so great 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 reparation of damaged nucleotides and ending suppression cell division).

Most studiedSOS reparationin E. coli, the main participants of which are proteins encoded genes Rec AAndLex A.

The first one is a multifunctionalRec A protein participating

V DNA recombination, and

V regulation of gene transcription phage lambdathat infects E. coli,

and second (Lex A protein)is repressor transcription of a large group of genes intended for DNA repair bacteria. When it is inhibited or resolved repair is activated.

Binding Rec A with Lex Aleads to the splitting of the latter and accordingly to activation of repair genes.

In turn, the induction of the bacterial SOS system serves tophage lambda danger signal and causes the prophage to switch from passive to active (lytic) path existence, thus causing host cell death.

The SOS repair system has been found not only in bacteria, but also in animals and humans.

Genes Involved in SOS DNA Damage Repair

Genes	Consequences of gene activation
uvr A, B, C, D	Repair of damage to the secondary structure of DNA
Rec A	Post-replicative repair, SOS system inductions
lex A	Turning off the SOS system
rec N, ruv	Repair of double strand breaks
	Ensuring recombination repair
umu C, D	Mutagenesis caused by changes in the properties of DNA polymerase
sul A	Suppression of cell division

Conclusion

Repairing DNA damage is closely related to other fundamental molecular genetic processes: replication, transcription and recombination. All these processes are intertwined into a common system of interactions served by a large number of diverse proteins, many of which are polyfunctional molecules involved in control over the implementation of genetic information in pro- and eukaryotic cells. At the same time, it is clear that nature "don't 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..

SCHEME OF NUCLEOTIDE EXCISION REPAIR IN E. COLIWITH THE PARTICIPATION OF EXINUCLEASE

1. A TRANSCRIPTIONLY INDEPENDENT MECHANISM

2. TRANSCRIPTION DEPENDENT MECHANISM

3. GENERAL STAGE OF REPAIR

SYMBOLS

A - proteinuvr A

B - proteinuvr IN

C - proteinuvr WITH

small black triangle - the sign indicates the location of damage

REPAIR SCHEME ASSOCIATED WITH DNA METHYLATION