DNA repair



  DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. Consequently, the DNA repair process must be constantly active so it can respond rapidly to any damage in the DNA structure.

The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:

  1. an irreversible state of dormancy, known as senescence
  2. cell suicide, also known as programmed cell death
  3. unregulated cell division, which can lead to the formation of a tumor that is cancerous

The DNA repair ability of a cell is vital to the integrity of its genome and thus to its normal functioning and that of the organism. Many genes that were initially shown to influence lifespan have turned out to be involved in DNA damage repair and protection.[2] Failure to correct molecular lesions in cells that form gametes can introduce mutations into the genomes of the offspring and thus influence the rate of evolution.

DNA damage

DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day.[1] While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell's ability to carry out its function and appreciably increase the likelihood of tumor formation.

The vast majority of DNA damage affects the histones (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage.

Sources of damage

DNA damage can be subdivided into two main types:

  1. endogenous damage such as attack by reactive oxygen species produced from normal metabolic byproducts (spontaneous mutation), especially the process of oxidative deamination;
  2. exogenous damage caused by external agents such as
    1. ultraviolet [UV 200-300nm] radiation from the sun
    2. other radiation frequencies, including gamma rays
    3. hydrolysis or thermal disruption
    4. certain plant toxins
    5. human-made intercalating agents
    6. cancer radiotherapy

The replication of damaged DNA before cell division can lead to the incorporation of wrong bases opposite damaged ones. Daughter cells that inherit these wrong bases carry mutations from which the original DNA sequence is unrecoverable (except in the rare case of a back mutation, for example, through gene conversion).

Types of damage

There are four main types of damage to DNA due to endogenous cellular processes:

  1. oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species,
  2. methylation), such as formation of 7-methylguanine, 1-methyladenine, O6 methylguanine
  3. hydrolysis of bases, such as deamination, depurination and depyrimidination.
  4. mismatch of bases, due to errors in DNA replication, in which the wrong DNA base is stitched into place in a newly forming DNA strand, or a DNA base is skipped over or mistakenly inserted.

Damage caused by exogenous agents comes in many forms. Some examples are:

  1. UV light causes crosslinking between adjacent cytosine and thymine bases creating pyrimidine dimers
  2. cosmic rays causes breaks in DNA strands.
  3. Thermal disruption at elevated temperature increases the rate of depurination (loss of purine residues per genome per generation) is too high in these species to be repaired by normal repair machinery, hence a possibility of an adaptive response cannot be ruled out.
  4. Industrial chemicals such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as polycyclic hydrocarbons found in smoke, soot and tar create a huge diversity of DNA adducts- ethenobases, oxidized bases, alkylated phosphotriesters and Crosslinking of DNA just to name a few.

UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage. Spontaneous damage can include the loss of a base, deamination, sugar ring puckering and tautomeric shift.

Nuclear versus mitochondrial DNA damage

In human cells, and eukaryotic cells in general, DNA is found in two cellular locations - inside the nucleus and inside the superoxide dismutase, which is present in both the mitochondria and cytoplasm of eukaryotic cells.

Senescence and apoptosis

Senescence, an irreversible state in which the cell no longer divides (mitosis), is a protective response to the shortening of the chromosome ends (noncoding DNA that cap chromosomes and undergo partial degradation each time a cell undergoes division (see Hayflick limit).[4] In contrast, quiescence is a reversible state of cellular dormancy that is unrelated to genome damage (see cell cycle). Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism,[5] which serves as a "last resort" mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth cellular signaling. Unregulated cell division can lead to the formation of a tumor (see cancer), which is potentially lethal to an organism. Therefore the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer.

DNA repair mechanisms

 

Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the genome (but cells remain superficially functional when so-called "non-essential" genes are missing or damaged). Depending on the type of damage inflicted on the DNA's double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister chromatid as a template to losslessly recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort.

Damage to DNA alters the spatial configuration of the helix and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules are summoned to, and bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place. The types of molecules involved and the mechanism of repair that is mobilized depend on the type of damage that has occurred and the phase of the cell cycle that the cell is in.

Direct reversal

Cells are known to eliminate three types of damage to their DNA by chemically reversing it. These mechanisms do not require a template, since the types of damage they counteract can only occur in one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone. The formation of thymine dimers (a common type of cyclobutyl dimer) upon irradiation with UV light results in an abnormal covalent bond between adjacent thymidine bases. The photoreactivation process directly reverses this damage by the action of the enzyme photolyase, whose activation is obligately dependent on energy absorbed from catalytic.[7] A generalized response to methylating agents in bacteria is known as the adaptive response and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes.[8] The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.

Single strand damage

  When only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. In order to repair damage to one of the two paired molecules of DNA, there exist a number of excision repair mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand.[7]

  1. Base excision repair (BER), which repairs damage to a single nucleotide caused by oxidation, alkylation, hydrolysis, or deamination. The base is removed with glycosylase and ultimately replaced by repair synthesis with DNA ligase.
  2. transcribed.
  3. Mismatch repair (MMR), which corrects errors of DNA replication and recombination that result in mispaired (but normal, that is non- damaged) nucleotides following DNA replication.

Double-strand breaks

Double-strand breaks (DSBs), in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. Two mechanisms exist to repair DSBs: non-homologous end joining (NHEJ) and recombinational repair (also known as template-assisted repair or homologous recombination repair).[7]   In NHEJ, DNA Ligase IV, a specialized T-cell receptors in the vertebrate immune system.[15]

Recombinational repair requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover during meiosis. This pathway allows a damaged chromosome to be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome as a template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the replication fork and are typically repaired by recombination.

supercoiling, which is especially common in regions near an open replication fork. Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.

A team of French researchers bombarded D-loop that can continue extension until they find complementary partner strands. In the final step there is crossover by means of RecA-dependent homologous recombination.[16]

Translesion synthesis

Translesion synthesis allows the DNA replication machinery to replicate past damaged DNA. This involves the use of specialized translesion UV irradiation, whereas Pol ζ introduces mutations at these sites. From the cell's perspective, the potential for introducing mutations during translesion synthesis is less dangerous than continuing the cell cycle with an incompletely replicated chromosome.

Global response to DNA damage

Cells exposed to apoptosis. The common features of global response are induction of multiple genes, cell cycle arrest, and inhibition of cell division.

DNA damage checkpoints

After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master BRCA1, MDC1, and 53BP1 has also been identified.[19] These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.

apoptosis following DNA damage.[20] At the G1/S checkpoint, p53 functions by deactivating the CDK2/cyclin E complex. Similarly, p21 mediates the G2/M checkpoint by deactivating the CDK1/cyclin B complex.

The prokaryotic SOS response

The repressor that binds to operator sequences commonly referred to as SOS boxes. It is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes.[21] The most common cellular signals activating the SOS response are regions of single stranded DNA (ssDNA), arising from stalled DNA helicase to separate the two DNA strands.[17] Once the DNA damage is repaired or bypassed using polymerases or through recombination, the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases cleavage activity of LexA homodimer which subsequently binds to the SOS boxes near promoters and restores normal gene expression.

Eukaryotic transcriptional responses to DNA damage

Eukaryotic cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, cell cycle checkpoint control, protein trafficking and degradation. Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of yeast Saccharomyces cerevisiae to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental shock response indicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the heterogeneity of mammalian cells. In an animal different types of cells are distributed amongst different organs which have evolved different sensitivities to DNA damage.[22]

In general global response to DNA damage involves expression of multiple genes responsible for postreplication repair, homologous recombination, nucleotide excision repair, DNA damage checkpoint, global transcriptional activation, genes controlling mRNA decay and many others. The vast amount of damage to a cell leaves it with an important decision; undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival which will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase η are members of [Y family translesion DNA polymerases present during global response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in eukaryotes.[17]

DNA repair and aging

Pathological effects of poor DNA repair

 

Experimental animals with genetic deficiencies in DNA repair often show decreased lifespan and increased cancer incidence. For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get lymphoma and infections more often, and consequently have shorter lifespans than wild-type mice.[23] Similarly, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan.[24] However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened lifespan without correspondingly higher rates of mutation.[25]

If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis or cancer. Inherited diseases associated with faulty DNA repair functioning result in premature aging, increased sensitivity to carcinogens, and correspondingly increased cancer risk (see The Low Level Radiation Campaign).

Longevity and caloric restriction

  A number of individual genes have been identified as influencing variations in lifespan within a population of organisms. The effects of these genes is strongly dependent on the environment, particularly on the organism's diet. Caloric restriction reproducibly results in extended lifespan in a variety of organisms, likely via nutrient sensing pathways and decreased metabolic rate. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see[27] for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction.

For example, increasing the gene dosage of the gene SIR-2, which regulates DNA packaging in the nematode worm Caenorhabditis elegans, can significantly extend lifespan.[28] The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction.[29] Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents,[30] although similar effects have not been observed in mitochondrial DNA.[31]

Interestingly, the C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended lifespan under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction.[32] This observation supports the pleiotropy theory of the biological origins of aging, which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life.

Medicine and DNA repair modulation

Hereditary DNA repair disorders

Defects in the NER mechanism are responsible for several genetic disorders, including:

  • xeroderma pigmentosum: hypersensitivity to sunlight/UV, resulting in increased skin cancer incidence and premature aging
  • Cockayne syndrome: hypersensitivity to UV and chemical agents
  • trichothiodystrophy: sensitive skin, brittle hair and nails

Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons.

Other DNA repair disorders include:

  • Werner's syndrome: premature aging and retarded growth
  • Bloom's syndrome: sunlight hypersensitivity, high incidence of malignancies (especially leukemias).
  • ataxia telangiectasia: sensitivity to ionizing radiation and some chemical agents

All of the above diseases are often called "segmental progerias" ("accelerated aging diseases") because their victims appear elderly and suffer from aging-related diseases at an abnormally young age.

Other diseases associated with reduced DNA repair function include Fanconi's anemia, hereditary breast cancer and hereditary colon cancer.

DNA repair and cancer

Inherited mutations that affect DNA repair genes are strongly associated with high cancer risks in humans. Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. BRCA2, two famous mutations conferring a hugely increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and homologous recombination.

Cancer therapy procedures such as radiotherapy work by overwhelming the capacity of the cell to repair DNA damage, resulting in cell death. Cells that are most rapidly dividing - most typically cancer cells - are preferentially affected. The side effect is that other non-cancerous but rapidly dividing cells such as stem cells in the bone marrow are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor) or by biochemical means (exploiting a feature unique to cancer cells in the body).

DNA repair and evolution

The basic processes of DNA repair are highly conserved among both prokaryotes and eukaryotes and even among bacteriophage (viruses that infect bacteria); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms.[33] The ability of a large number of protein structural motifs to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see.[34]

The fossil record indicates that single celled life began to proliferate on the planet at some point during the Precambrian period, although exactly when recognizably modern life first emerged is unclear. oxidative stress.

Rate of evolutionary change

On some occasions, DNA damage is not repaired, or is repaired by an error-prone mechanism which results in a change from the original sequence. When this occurs, mutations may propagate into the genomes of the cell's progeny. Should such an event occur in a germ line cell that will eventually produce a gamete, the mutation has the potential to be passed on to the organism's offspring. The rate of evolution in a particular species (or, more narrowly, in a particular gene) is a function of the rate of mutation. Consequently, the rate and accuracy of DNA repair mechanims have an influence over the process of evolutionary change.[35]

See also

  • Accelerated aging disease
  • Aging DNA
  • Cell cycle
  • DNA replication
  • Gene therapy
  • Life extension
  • Human mitochondrial genetics
  • Progeria
  • Senescence

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