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DNA repair

2007 Schools Wikipedia Selection. Related subjects: General Biology

   DNA damage resulting in multiple broken chromosomes
   DNA damage resulting in multiple broken chromosomes

   DNA repair refers to a collection of processes by which a cell
   identifies and corrects damage to the DNA molecules that encode its
   genome. In human cells, both normal metabolic activities and
   environmental factors such as UV light can cause DNA damage, resulting
   in as many as 1 million individual molecular lesions per cell per day.
   Many of these lesions cause structural damage to the DNA molecule and
   can alter or eliminate the cell's ability to transcribe the gene that
   the affected DNA encodes. Other lesions induce potentially harmful
   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 by its DNA, can enter one of
   three possible states:
    1. an irreversible state of dormancy, known as senescence
    2. cell suicide, also known as apoptosis or 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. 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. 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 primary structure of the
   double helix; that is, the bases themselves are chemically modified.
   These modifications can in turn disrupt the molecules' regular helical
   structure by introducing non-native chemical bonds or bulky adducts
   that do not fit in the standard double helix. Unlike proteins and RNA,
   DNA usually lacks secondary structure and therefore damage or
   disturbance does not occur at that level. DNA is, however, supercoiled
   and wound around "packaging" proteins called histones, and both
   superstructures are vulnerable to the effects of DNA damage.

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. alkylation of bases (usually methylation), such as formation of
       7-methylguanine
    3. hydrolysis of bases, such as deamination, 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.

   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. Ionizing radiation such as that created by radioactive decay or in
       cosmic rays causes breaks in DNA strands
    3. 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 and alkylated phosphotriesters, just to
       name a few.

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. Nuclear DNA
   (nDNA) exists as chromatin during non-replicative stages of the cell
   cycle and is condensed into aggregate structures known as chromosomes
   during cell division. In either state the DNA is highly compacted and
   wound up around bead-like proteins called histones. Whenever a cell
   needs to express the genetic information encoded in its nDNA the
   required chromosomal region is unravelled, genes located therein are
   expressed, and then the region is condensed back to its resting
   conformation. Mitochondrial DNA (mtDNA) is located inside mitochondria
   organelles, exists in multiple copies, and is also tightly associated
   with a number of proteins to form a complex known as the nucleoid.
   Inside mitochondria, reactive oxygen species (ROS), or free radicals,
   byproducts of the constant production of adenosine triphosphate (ATP)
   via oxidative phosphorylation, create a highly oxidative environment
   that is known to damage mtDNA. A critical enzyme in counteracting the
   toxicity of these species is 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 ( telomeres). The telomeres are long regions of repetitive
   noncoding DNA that cap chromosomes and undergo partial degradation each
   time a cell undergoes division (see Hayflick limit). 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,
   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.
   Single strand and double strand DNA damage
   Single strand and double strand DNA damage

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. 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 in bacteria directly reverses this damage by the action of the
   enzyme photolyase, which uses energy absorbed from UV light to promote
   catalysis. Another type of damage, methylation of guanine bases, is
   directly reversed by the protein methyl guanine methyl transferase
   (MGMT). This is an expensive process because each MGMT molecule can
   only be used once; that is, the reaction is stoichiometric rather than
   catalytic. 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.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.
    1. Base excision repair (BER), which repairs damage due to a single
       nucleotide caused by oxidation, alkylation, hydrolysis, or
       deamination;
    2. Nucleotide excision repair (NER), which 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;
    3. Mismatch repair (MMR), which corrects errors of DNA replication and
       recombination that result in mispaired nucleotides following DNA
       replication.

Double strand breaks

   A type of DNA damage particularly hazardous to dividing cells is a
   break to both strands in the double-helix. Two mechanisms exist to
   repair this damage. They are generally known as non-homologous
   end-joining (NHEJ) and recombinational repair (also known as
   template-assisted repair or homologous recombination repair).

   The NHEJ pathway operates when the cell has not yet replicated the
   region of DNA on which the lesion has occurred. The process directly
   joins the two ends of the broken DNA strands without a template, losing
   sequence information in the process. Thus this repair mechanism is
   necessarily mutagenic. However, if the cell is not dividing and has not
   replicated its DNA, the NHEJ pathway is the cell's only option. NHEJ
   relies on chance pairings, or microhomologies, between the
   single-stranded tails of the two DNA fragments to be joined. There are
   multiple independent "failsafe" pathways for NHEJ in higher eukaryotes.

   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
   the newly created sister chromatid as a template, i.e. an identical
   copy that is also linked to the damaged region via the centromere.
   Double-stranded breaks repaired by this mechanism are usually caused by
   the replication machinery attempting to synthesize across a
   single-strand break or unrepaired lesion, both of which result in
   collapse of the replication fork.

   It should be noted that topoisomerases sometimes introduce both single
   and double strand breaks in the course of changing the DNA's state of
   supercoiling, which is especially common in regions near an open
   replication fork. Such breaks are not considered DNA damage because
   they serve a biochemical purpose and are immediately repaired by the
   enzymes that created them.

   A team of French researchers bombarded Deinococcus radiodurans to study
   the mechanism of double-strand break DNA repair in that organism. At
   least two copies of the genome, with random DNA breaks, can form DNA
   fragments through annealing. Partially overlapping fragments are then
   used for synthesis of homologous regions through a moving 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.

Translesion synthesis

   Translesion synthesis is an error-prone (almost error-guaranteeing)
   last-resort method of repairing a DNA lesion that has not been repaired
   by any other mechanism. The DNA replication machinery cannot continue
   replicating past a site of DNA damage, so the advancing replication
   fork will stall on encountering a damaged base. The translesion
   synthesis pathway is mediated by specific DNA polymerases that insert
   extra bases at the site of damage and thus allow replication to bypass
   the damaged base to continue with chromosome duplication. From the
   cell's perspective, it is "better" to introduce mutations around a
   single site than to continue the cell cycle with an incompletely
   replicated chromosome. The bases inserted by the translesion synthesis
   machinery are template-independent, but not arbitrary; for example, one
   human polymerase inserts adenine bases when synthesizing past a thymine
   dimer.

DNA repair and aging

Poor DNA repair induces pathology

   DNA repair rate is an important determinant of cell pathology
   DNA repair rate is an important determinant of cell pathology

   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. 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. 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.

   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 below). On the other hand, organisms with enhanced DNA repair
   systems, such as Deinococcus radiodurans, the most radiation-resistant
   known organism, exhibit remarkable resistance to the double strand
   break-inducing effects of radioactivity, likely due to enhanced
   efficiency of DNA repair and especially NHEJ. It is noteworthy that
   some workers suggest that if a DNA damage event occurs during the self
   repair process then the combination of the two events will exert an
   effect greater than the sum of the individual events (if they occurred
   with a long time delay between them), this is the basis of the second
   event theory favoured by C. Busby ( The Low Level Radiation Campaign).

Longevity and caloric restriction

   Most lifespan influencing genes affect the rate of DNA damage
   Most lifespan influencing genes affect the rate of DNA damage

   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 for some discussion); however, the behaviour 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. 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. Caloric restriction has been closely linked to the rate of
   base excision repair in the nuclear DNA of rodents, although similar
   effects have not been observed in mitochondrial DNA.

   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. 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 anaemia, 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. BRCA1 and 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 chemotherapy and 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

An Ancient and Conserved Mechanism

   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. 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 .

   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. Nucleic acids became the sole and universal means of encoding
   genetic information, requiring DNA repair mechanisms that in their
   basic form have been inherited by all extant life forms from their
   common ancestor. The emergence of Earth's oxygen-rich atmosphere (known
   as the " oxygen catastrophe") due to photosynthetic organisms, as well
   as the presence of potentially damaging free radicals in the cell due
   to oxidative phosphorylation, necessitated the evolution of DNA repair
   mechanisms that act specifically to counter the types of damage induced
   by oxidative stress.

Evolutionary rate as a function of DNA repair rate

   When DNA damage is not repaired properly, or is repaired by an
   error-prone mechanism, mutations are introduced into the genomes of the
   cell's progeny. When this occurs in a germ line cell that will
   eventually produce a gamete, the mutation is passed on to the affected
   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 and thus of the accuracy and the rate of the DNA repair
   pathway and factors that can influence it.

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