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DNA repair

Sunday 13 July 2003

Definition: DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome.

See also

- DNA repair genes (DRGs)

The carrier rate of germline BRCA1/2 and ATM mutation was ∼5-fold higher in lethal prostate cancer patients than in localized prostate cancer patients. doi : 10.1016/j.eururo.2016.11.033

Mutation carriers of BRCA1/2 and ATM are associated with earlier age at death and shorter survival time. doi : 10.1016/j.eururo.2016.11.033

DNA repair is a process constantly operating in cells; it is essential to survival because it protects the genome from DNA damage and harmful mutations.

The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment.

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.

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.

The inability to repair DNA damage properly in mammals leads to various disorders and enhanced rates of tumour development. Organisms respond to DNA insults by activating a complex damage response pathway. This pathway regulates known responses such as cell-cycle arrest and apoptosis (programmed cell death), and control additional processes including direct activation of DNA repair networks.

The survival of organism depends on the accurate transmission of genetic information from one cell to its daughters. Such faithful transmission requires not only extreme accuracy in replication of DNA and precision in chromosome distribution, but also the ability to survive spontaneous and induced DNA damage while minimizing the number of heritable mutations.

To achieve this fidelity, cells have evolved surveillance mechanisms that monitor the structure of chromosomes and coordinate repair and cell cycle progression.

BER (Base Excision Repair) is the main guardian against the most frequent types of DNA damage due to cellular metabolism, including that resulting from ROS (Reactive Oxygen Species), methylation, deamination, hydroxylation or spontaneous loss of the DNA base itself.

These alterations, although simple in nature, are highly mutagenic and therefore represent a significant threat to genome fidelity and stability.

DNA damage - DNA lesions

In human cells, both normal metabolic activities and environmental factors (such as UV rays) can cause DNA damage, resulting in as many as 500,000 individual molecular lesions per cell per day. These DNA lesions cause structural damage to the DNA molecule, and can dramatically alter the cell’s way of reading the information encoded in its genes. Consequently, the DNA repair process must be constantly operating, to correct rapidly any damage in the DNA structure.

As cells age, however, the rate of DNA repair decreases until it can no longer keep up with ongoing DNA damage. The cell then suffers one of three possible fates:

- an irreversible state of dormancy, known as senescence
- cell apoptosis or programmed cell death
- carcinogenesis (formation of cancer)

Most cells in the body first become senescent. Then, after irreparable DNA damage, apoptosis occurs. In this case, apoptosis functions as a "last resort" mechanism to prevent a cell from becoming carcinogenic (able to form a tumor - see cancer) and endangering the organism.

When cells become senescent, alterations in biosynthesis and turnover cause them to function less efficiently, which inevitably causes disease.

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.

Failure to correct molecular lesions in cells that form gametes leads to mutated progeny and can thus influence the rate of evolution.

DNA repair genes and proteins

DNA repair genes affect cell proliferation or survival indirectly by influencing the ability of the organism to repair nonlethal damage in other genes, including protooncogenes, tumor suppressor genes, and genes that regulate apoptosis.

A disability in the DNA repair genes can predispose to mutations in the genome and hence to neoplastic transformation. Such propensity to mutations is called a mutator phenotype.

With some exceptions, both alleles of DNA repair genes must be inactivated to induce such genomic instability; in this sense, DNA repair genes may also be considered as tumor suppressor genes.

DNA repair pathways

- 1. DNA single-strand break repair

- 2. DNA double-strand break repair
- 3. DNA mismatch repair
- 4. Transcription-coupled repair (TCR)

- 1. DNA single-strand break repair

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.

Among the DNA repair mechanisms that operate in response to the presence of base damage in DNA, three biochemical pathways result in the excision of damaged or inappropriate bases. These are called base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR).

  • 1a. base excision repair (BER) 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.
  • 1b. nucleotide excision repair (NER) repairs damage affecting longer strands of 2–30 bases. This process recognizes bulky, helix-distorting changes such as thymine dimers as well as single-strand breaks (repaired with enzymes such UvrABC endonuclease). A specialized form of NER known as Transcription-Coupled Repair (TCR) deploys high-priority NER repair enzymes to genes that are being actively transcribed.
  • 1c. mismatch repair (MMR) corrects errors of DNA replication and recombination that result in mispaired (but normal, that is non- damaged) nucleotides following DNA replication.

DNA repair and evolution

One form of DNA damage is alteration of a nucleotide (a mutation), altering the information carried in the DNA sequence. Because DNA mutation and recombination are the main means for evolution to occur, the rate of DNA repair influences the rate of evolution.

With a very high level of DNA repair rate, the rate of mutation is reduced, resulting in corresponding reduction in the rate of evolution. Conversely, high mutation rates increase the rate of evolution.

From a geologic chronological perspective, DNA repair mechanisms evolved during the Precambrian period not long after the life began to use nucleic acids as a means of encoding genetic information.

During this period atmospheric oxygen began to increase steadily and then with the explosion of photosynthetic plants during the Cambrian period the levels approximated those that we have today.

The toxicity of oxygen due to the formation of free radicals required the evolution of mechanisms able to reduce and repair such damage. Today, we can see highly conserved mechanisms of DNA repair that humans share with species as diverse as flies and worms.

Pathology (Anomalies of DNA repair - DNA repair diseases)

- DNA repair and diseases

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 senescence, apoptosis or cancer.

- Poor DNA repair and aging

As cells get older, the amount of DNA damage accumulates overtaking the rate of repair and resulting in a reduction of protein synthesis.

As proteins in the cell are used for numerous vital functions, the cell becomes slowly impaired and eventually dies. When enough cells in an organ reach such a state, the organ itself will become compromised and the symptoms of disease begin to manifest.

Experimental studies in animals, where genes associated with DNA repair were silenced, resulted in accelerated aging, early manifestation of age related diseases and increased susceptibility to cancer.

In studies where the expression of certain DNA repair genes was increased resulted in extended lifespan and resistance to carcinogenic agents in cultured cells.

- Hereditary DNA repair disorders (Genetic diseases of DNA repair pathways)

  • DNA single-strand break repair diseases
  • DNA double-strand break repair diseases
  • DNA mismatch repair diseases
  • transcription-coupled repair diseaases (TCR diseases)
  • RecQ helicase deficiencies
  • base excision repair deficiency (BER diseases)
  • nucleotide excision repair (NER diseases)
    • xeroderma pigmentosum
    • Cockayne syndrome
    • trichothiodystrophy

Interestingly, most 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.

- Chronic DNA repair disorders

Chronic disease can be associated with increased DNA damage. For example, smoking cigarettes causes oxidative damage to the DNA and other components of heart and lung cells, resulting in the formation of DNA adducts (molecules that disrupt DNA). DNA damage has now been shown to be a causative factor in diseases from atherosclerosis to Alzheimer’s, where patients have a lesser capacity for DNA repair in their brain cells. Mitochondrial DNA damage has also been implicated in numerous disorders.

- Longevity genes and DNA repair

Most lifespan influencing genes affect the rate of DNA damageCertain genes are known to influence variation in lifespan within a population of organisms. Studies in model organisms such as yeast, worms, flies and mice have identified single genes, which when modified, can double lifespan (eg. a mutation in the age-1 gene of the nematode Caenorhabditis elegans).

These genes are known to be associated specifically with cell functions other than DNA repair, but when the pathways that they influence are followed to their final destination, it was observed that they mediate one of three functions: increasing the rate of DNA repair, increasing the rate of antioxidant production, or
decreasing the rate of oxidant production.

Therefore, the common pattern across most lifespan influencing genes is in their downstream effect of altering the rate of DNA damage.

- Caloric restriction increases DNA repair

Caloric restriction (CR) has been shown to increase lifespan and decrease age related disease in all organisms where it has been studied, from single celled life such as yeast, to multicellular organisms such as worms, flies, mice and primates.

The mechanism by which CR works is associated with a number of genes related to nutrient sensing which signal the cell to alter metabolic activity when there is a shortage of nutrients, particularly carbohydrates.

When the cell senses a decrease in carbohydrate availability, activation of the lifespan influencing genes DAF-2, AGE-1 and SIR-2 is triggered.

The reason why a shortage of nutrients will induce in a cell a state of increased DNA repair and an increase in lifespan is suggested to be associated with an evolutionarily conserved mechanism of cellular hibernation.

Essentially this permits a cell to maintain a dormant state until conditions that are more favorable are met. During this period, the cell must decrease its normal rate of metabolism and one of the ways it can accomplish this is by reducing genomic instability.

Thus, the cellular rate of aging is mutable and can be influenced by environmental factors such as nutrient availability, which mediate their effect by altering the rate of DNA repair.

See also

- DNA damage checkpoints
- cellular cycle checkpoints

Videos

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