DNA repair

From Academic Kids

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DNA damage resulting in multiple broken chromosomes

DNA repair is a process constantly operating in each cell of a living being; it is essential to survival because it protects the genome from damage. 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 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 can no longer keep up with ongoing DNA damage. The cell then suffers one of three possible fates:

  1. an irreversible state of dormancy, known as senescence
  2. cell suicide, also known as apoptosis or programmed cell death
  3. cancer

Most cells in the body 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 cancerous and endangering the organism.

When cells become senescent, alterations in their gene regulation cause them to function less efficiently, which inevitably causes disease. The DNA repair ability of a cell is vital to its normal functioning and to the health and longevity of the organism. Many genes that were shown to influence lifespan were subsequently associated with DNA damage repair and protection.

Failure to correct lesions in cells that form gametes cause mutations from one generation to the next, and hence influence the rate of evolution.

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Contents

DNA damage

DNA damage, due to normal metabolic processes inside the cell, occurs at a rate of 50,000 to 500,000 molecular lesions per cell per day. However, many more sources of damage can drive this number even higher. Whilst this constitutes only 0.0002% of the human genome of 3,000,000,000 (3 billion) bases, a single unrepaired lesion to a critical cancer related gene (such as a tumor suppressor gene) could have catastrophic consequences for the cell.

Nuclear versus mitochondrial DNA damage

In human, and eukaryotic cells in general, DNA is found in two cellular locations - inside the nucleus and inside the mitochondria (mitochondrial genetics). Nuclear DNA (nDNA) exists in large scale aggregate structures known as chromosomes which are composed of DNA wound up around bead-like proteins called histones. Whenever the cell needs to access the genetic information encoded in nDNA it will unravel the required section, read it, and then allow it to wind up once more in its protected conformation. In contrast, mitochondrial DNA (mtDNA) which is located inside mitochondria organelles, exists in single or multiple copies of a circular loop without any histone association. Consequently, mtDNA is far more prone to damage than nDNA because it lacks the structural protection afforded by histone proteins. In addition, the highly oxidative environment inside mitochondria that exists due to the constant production of adenosine triphosphate (ATP) via oxidative phosphorylation makes mtDNA even more prone to damage.

Sources of damage

DNA damage can be subdivided into two main types:

  1. endogenous processes such as attack by reactive oxygen radicals produced from normal metabolic byproducts (spontaneous mutation);
  2. agents of environmental origin, such as
    1. Ultraviolet [UV 200-300nm] radiation from the sun
    2. other radiation frequencies, including x-rays and gamma rays
    3. certain plant toxins
    4. human-made mutagenic chemicals, such as hydrocarbons from cigarette smoke
    5. cancer chemotherapy and radiotherapy

Replication of damaged DNA can lead to the incorporation of the wrong base opposite the damaged one. This "incorrect" base is now fixed in the next generation cell, permanently changing the DNA sequence. This change in sequence is a mutation.

Types of damage

Endogenous damage affects the primary rather than secondary structure of the double helix. It can be subdivided into four classes:

  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 of bases, such as formation of 7-methylguanine
  3. hydrolysis of bases, such as depurination and depyrimidination.
  4. mismatch of bases, due to DNA replication in which the wrong DNA base is stitched into place in a newly forming DNA strand.

DNA repair mechanisms

The cell cannot tolerate DNA damage as it interferes with the integrity and accessibility of the information encoded in its genome. Depending on the type of damage inflicted on the DNA's double helical structure, a variety of repair strategies have evolved to replace the lost information. The information to be replaced must be made available either by an intact version from the complementary strand of DNA or from the sister chromosome. Without access to this information repair cannot take place.

Damaged DNA results in an altered configuration of the molecule which can be rapidly detected by the cell. Specific DNA repair related molecules are attracted to and bind at or near the site of damage inducing other molecules also to bind and form a complex that enables repair to take place. The types of molecules involved and the mechanism of repair that takes place is based on:

  1. the type of damage on the DNA molecule
  2. whether the cell has entered into a state of senescence
  3. the phase of the cell cycle that the cell is in
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Single strand and double strand DNA damage

Single strand damage

In order to repair damage to one of the two helical domains of DNA, there are numerous mechanisms by which DNA repair can take place. These include:

  1. direct reversal of damage are specialized mechanisms for the reversing of one specific type of damage. Examples include methyl guanine methyl transferase (MGMT) which specifically removes methyl groups from guanine or photolyase in bacteria, which breaks the chemical bond created by UV light between adjacent thymidine bases.
  2. Excision repair mechanisms in which the damaged nucleotide is removed and an undamaged nucleotide put back in by using the information from the undamaged copy. These include:
    1. base excision repair (BER), which repairs damage due to alkylation or deamination;
    2. nucleotide excision repair (NER), which largely repairs bulky, helix distorting damage, including damage caused by UV light; and
    3. mismatch repair (MMR), which corrects errors of DNA replication and recombination
  3. single strand break repair, which rejoins interruptions in a single strand of the DNA chain caused by oxidation.

Double strand breaks

A particularly hazardous type of DNA damage to dividing cells is a break to both strands in the double helix. There are two mechanisms that exist to repair this damage. They are generally known as homologous recombination and Non-Homologous End-Joining.

Homologous recombination utilizes a source of identical or nearly identical sequence in the genome as a template for repair of the break. This mechanism is believed to be predominantly used during the phases of the cell cycle when the DNA is replicating or has completed replicating it's DNA. This allows a damaged chromosome to be repaired using the newly created sister chromatid which is an identical copy. The human genome is highly repetative and contains many possible sources of identical sequences. Recombination with these other sequences can be very harmful since the crossing over which may result, can cause a chromosomal translocation or other chromosome rearrangements. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover in germ cells during meiosis.

Non-Homologous End-Joining (NHEJ) essentially rejoins the two ends of the break, however there is often DNA sequence lost during this process and so this repair can be mutagenic. NHEJ can occur at all stages of the cell cycle but is predominant before DNA replication when homologous recombination with the sister chromatid is not yet availble. Since the vast majority of the genome in humans and other multicellular organisms is made up of DNA which are not genes, the so-called "junk DNA", this mutagenic repair is less likely to be harmful to a cell than homologous recombination with sequences other than the sister chromatid. The enzymatic machinery used for NHEJ is also utilized in B-cells to rejoin breaks created by the RAG proteins during VDJ recombination in the generation of antibodies in the immune system.

See also Carcinogenesis (http://carcin.oupjournals.org/cgi/content/full/23/5/687)

DNA repair in disease and aging

Poor DNA repair induces pathology

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DNA repair rate is an important determinant of cell pathology

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.

DNA repair rate is variable

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. Inherited diseases associated with faulty DNA repair functioning result in premature aging (e.g. Werner's syndrome) and increased sensitivity to carcinogens (e.g Xeroderma Pigmentosum). Studies in animals, where DNA repair genes are prevented from functioning, show similar disease profiles.

On the other hand, organisms with enhanced DNA repair systems, such as Deinococcus radiodurans (also known as "Conan the bacterium", listed in the Guinness Book of World Records as "the world's toughest bacterium"), exhibit remarkable resistance to radioactivity, because their DNA repair enzymes are able to perform at unusually fast rates to keep up with radiation induced-damage, and because it carries 4–10 copies of the genome. In human studies, Japanese centenarians have been found to have a common mitochondrial genotype, which predisposes them to reduced DNA damage in their mitochondria.

Studies in smokers have found that, for people with a mutation that causes them to express less of the powerful DNA repair gene hOGG1, their vulnerability to lung and other smoking related cancers are increased. Single nucleotide polymorphisms (SNP) associated with this mutation can be clinically detected.

Hereditary DNA repair disorders

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

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

Other DNA repair disorders include:

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

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

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Most lifespan influencing genes affect the rate of DNA damage

Certain 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:

  1. increasing the rate of DNA repair,
  2. increasing the rate of antioxidant production, or
  3. 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 (see accompanying illustration "Most lifespan influencing genes affect the rate of DNA damage") 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 more favorable conditions 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.

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.

DNA repair mechanisms are ancient

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.

Disease, death and evolution

DNA repair rates play a vital role at the cellular scale of (non-infectious) disease and aging, and at the population scale of evolution. Two important relationships have been established:

  1. DNA repair rate and mutation
  2. DNA repair rate and aging

As mutation is directly related to evolution, a new way of looking at the relationship between evolution and aging emerges. It is apparent that, while the mechanism of mutation provides the genome the plasticity to adapt, it is also responsible for destabilizing it, as well as for rendering it vulnerable to disease and aging. Are organisms subject to disease and aging primarily because mutation is the primary driver of evolution? This remains a contentious issue and numerous theories of aging have been offered.

Medicine & DNA repair modulation

There is a vast body of evidence that has correlated DNA damage to death and disease. As indicated by new overexpression studies, increasing the activity of some DNA repair enzymes could decrease the rate of aging and disease. This may result in the development of human interventions that can add many healthy and disease-free years to an aging population. Not all DNA repair enzymes are beneficial when overexpressed, however. Some DNA repair enzymes can introduce new mutations in healthy DNA. Reduced substrate specificity has been implicated in these errors.

Cancer treatment

Procedures such as chemotherapy and radiotherapy work by overwhelming the capacity of the cell to repair DNA damage and resulting in cell death. Cells that are most rapidly dividing such as cancer cells are preferentially affected. The side effect is that other non-cancerous but similarly 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.

Gene therapy

For therapeutic uses of DNA repair, the challenge is to discover which particular DNA repair enzymes exhibit the most precise specificity for damaged sites, so its overexpression will lead to enhanced DNA repair function. Once the appropriate repair factors have been identified, the next step is in selecting the appropriate way to deliver them into cells, to generate viable disease and aging treatments. The development of smart genes, which are able to alter the amount of protein they produce based on changing cellular conditions, stand to increase the efficacy of DNA repair augmentation treatments.

Gene repair

Unlike the multiple mechanisms of endogenous DNA repair, gene repair (or gene correction) refers to a form of gene therapy, which precisely targets and corrects chromosomal mutations responsible for a disorder. It does so by replacing the flawed DNA sequence with the desired sequence, using techniques such as oligonucleotide-directed mutagenesis. Genetic mutations requiring repair are normally inherited, but in some cases they can also be induced or acquired (such as in cancer).

References

  • S. Tornaletti and G. P. Pfeiffer (1996) UV damage and repair mechanisms in mammalian cells. Bioessays 18, 221–228.

External links

ja:DNA修復

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