DNA repair is 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 and radiation 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. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages (interstrand crosslinks or ICLs). This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.
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:
- an irreversible state of dormancy, known as senescence
- cell suicide, also known as apoptosis or programmed cell death
- 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 the normal functionality of that organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection.
- 1 DNA damage
- 2 DNA repair mechanisms
- 3 Global response to DNA damage
- 4 DNA repair and aging
- 5 Medicine and DNA repair modulation
- 6 DNA repair and cancer
- 7 DNA repair and evolution
- 8 DNA repair technology
- 9 See also
- 10 References
- 11 External links
DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 10,000 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 and contribute to tumour heterogeneity.
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 tertiary structure and therefore damage or disturbance does not occur at that level. DNA is, however, supercoiled and wound around "packaging" proteins called 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:
- endogenous damage such as attack by reactive oxygen species produced from normal metabolic byproducts (spontaneous mutation), especially the process of oxidative deamination
- also includes replication errors
- exogenous damage caused by external agents such as
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 several types of damage to DNA due to endogenous cellular processes:
- oxidation of bases [e.g. 8-oxo-7,8-dihydroguanine (8-oxoG)] and generation of DNA strand interruptions from reactive oxygen species,
- alkylation of bases (usually methylation), such as formation of 7-methylguanosine, 1-methyladenine, 6-O-Methylguanine
- hydrolysis of bases, such as deamination, depurination, and depyrimidination.
- "bulky adduct formation" (i.e., benzo[a]pyrene diol epoxide-dG adduct, aristolactam I-dA adduct)
- 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.
- Monoadduct damage cause by change in single nitrogenous base of DNA
- Diadduct damage
Damage caused by exogenous agents comes in many forms. Some examples are:
- UV-B light causes crosslinking between adjacent cytosine and thymine bases creating pyrimidine dimers. This is called direct DNA damage.
- UV-A light creates mostly free radicals. The damage caused by free radicals is called indirect DNA damage.
- Ionizing radiation such as that created by radioactive decay or in cosmic rays causes breaks in DNA strands. Intermediate-level ionizing radiation may induce irreparable DNA damage (leading to replicational and transcriptional errors needed for neoplasia or may trigger viral interactions) leading to pre-mature aging and cancer.
- Thermal disruption at elevated temperature increases the rate of depurination (loss of purine bases from the DNA backbone) and single-strand breaks. For example, hydrolytic depurination is seen in the thermophilic bacteria, which grow in hot springs at 40-80 °C. The rate of depurination (300 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.
- Industrial chemicals such as vinyl chloride and hydrogen peroxide, and environmental chemicals such as polycyclic aromatic 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 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 process in which the cell no longer divides, is a protective response to the shortening of the chromosome ends. 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 damage and mutation
It is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA damages and mutation are fundamentally different. Damages are physical abnormalities in the DNA, such as single- and double-strand breaks, 8-hydroxydeoxyguanosine residues, and polycyclic aromatic hydrocarbon adducts. DNA damages can be recognized by enzymes, and, thus, they can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented, and, thus, translation into a protein will also be blocked. Replication may also be blocked or the cell may die.
In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and, thus, a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair; these errors are a major source of mutation.
Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cell's survival. Thus, in a population of cells composing a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can give rise to cancer. Thus, DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are likely a prominent cause of aging.
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 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 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 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.
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 occur in only 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 pyrimidine dimers upon irradiation with UV light results in an abnormal covalent bond between adjacent pyrimidine bases. The photoreactivation process directly reverses this damage by the action of the enzyme photolyase, whose activation is obligately dependent on energy absorbed from blue/UV light (300–500 nm wavelength) to promote catalysis. Photolyase, an old enzyme present in bacteria, fungi, and most animals no longer functions in humans, who instead use nucleotide excision repair to repair damage from UV irradiation. Another type of damage, methylation of guanine bases, is directly reversed by the protein methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called ogt. This is an expensive process because each MGMT molecule can be used only 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 by upregulation of alkylation repair enzymes. The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.
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.
- Base excision repair (BER) repairs damage to a single nitrogenous base by deploying enzymes called glycosylases. These enzymes remove a single nitrogenous base to create an apurinic or apyrimidinic site (AP site). Enzymes called AP endonucleases nick the damaged DNA backbone at the AP site. DNA polymerase then removes the damaged region using its 5’ to 3’ exonuclease activity and correctly synthesizes the new strand using the complementary strand as a template.
- Nucleotide excision repair (NER) repairs damaged DNA which commonly consists of bulky, helix-distorting damage, such as pyrimidine dimerization caused by UV light. Damaged regions are removed in 12-24 nucleotide-long strands in a three-step process which consists of recognition of damage, excision of damaged DNA both upstream and downstream of damage by endonucleases, and resynthesis of removed DNA region. NER is a highly evolutionarily conserved repair mechanism and is used in nearly all eukaryotic and prokaryotic cells. In prokaryotes, NER is mediated by Uvr proteins. In eukaryotes, many more proteins are involved, although the general strategy is the same.
- Mismatch repair systems are present in essentially all cells to correct errors that are not corrected by proofreading. These systems consist of at least two proteins. One detects the mismatch, and the other recruits an endonuclease that cleaves the newly synthesized DNA strand close to the region of damage. In E. coli , the proteins involved are the Mut class proteins. This is followed by removal of damaged region by an exonuclease, resynthesis by DNA polymerase, and nick sealing by DNA ligase.
Double-strand breaks, in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. Three mechanisms exist to repair double-strand breaks (DSBs): non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination. PVN Acharya noted that double-strand breaks and a "cross-linkage joining both strands at the same point is irreparable because neither strand can then serve as a template for repair. The cell will die in the next mitosis or in some rare instances, mutate."
In NHEJ, DNA Ligase IV, a specialized DNA ligase that forms a complex with the cofactor XRCC4, directly joins the two ends. To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate. NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms insertions or translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are "backup" NHEJ pathways in higher eukaryotes. Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during V(D)J recombination, the process that generates diversity in B-cell and T-cell receptors in the vertebrate immune system.
MMEJ starts with short-range end resection by MRE11 nuclease on either side of a double-strand break to reveal microhomology regions. In further steps, PARP1 is required and may be an early step in MMEJ. There is pairing of microhomology regions followed by recruitment of flap structure-specific endonuclease 1 (FEN1) to remove overhanging flaps. This is followed by recruitment of XRCC1–LIG3 to the site for ligating the DNA ends, leading to an intact DNA.
DNA double strand breaks in mammalian cells are primarily repaired by homologous recombination (HR) and non-homologous end joining (NHEJ). In an in vitro system, MMEJ occurred in mammalian cells at the levels of 10–20% of HR when both HR and NHEJ mechanisms were also available. MMEJ is always accompanied by a deletion, so that MMEJ is a mutagenic pathway for DNA repair.
Homologous recombination 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.
Topoisomerases 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 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 Deinococcus radiodurans to study the mechanism of double-strand break DNA repair in that bacterium. 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 (TLS) is a DNA damage tolerance process that allows the DNA replication machinery to replicate past DNA lesions such as thymine dimers or AP sites. It involves switching out regular DNA polymerases for specialized translesion polymerases (i.e. DNA polymerase IV or V, from the Y Polymerase family), often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase switching is thought to be mediated by, among other factors, the post-translational modification of the replication processivity factor PCNA. Translesion synthesis polymerases often have low fidelity (high propensity to insert wrong bases) on undamaged templates relative to regular polymerases. However, many are extremely efficient at inserting correct bases opposite specific types of damage. For example, Pol η mediates error-free bypass of lesions induced by UV irradiation, whereas Pol ι introduces mutations at these sites. Pol η is known to add the first adenine across the T^T photodimer using Watson-Crick base pairing and the second adenine will be added in its syn conformation using Hoogsteen base pairing. From a cellular perspective, risking the introduction of point mutations during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may cause gross chromosomal aberrations or cell death. In short, the process involves specialized polymerases either bypassing or repairing lesions at locations of stalled DNA replication. For example, Human DNA polymerase eta can bypass complex DNA lesions like guanine-thymine intra-strand crosslink, G[8,5-Me]T, although can cause targeted and semi-targeted mutations. Paromita Raychaudhury and Ashis Basu studied the toxicity and mutagenesis of the same lesion in Escherichia coli by replicating a G[8,5-Me]T-modified plasmid in E. coli with specific DNA polymerase knockouts. Viability was very low in a strain lacking pol II, pol IV, and pol V, the three SOS-inducible DNA polymerases, indicating that translesion synthesis is conducted primarily by these specialized DNA polymerases. A bypass platform is provided to these polymerases by Proliferating cell nuclear antigen (PCNA). Under normal circumstances, PCNA bound to polymerases replicates the DNA. At a site of lesion, PCNA is ubiquitinated, or modified, by the RAD6/RAD18 proteins to provide a platform for the specialized polymerases to bypass the lesion and resume DNA replication. After translesion synthesis, extension is required. This extension can be carried out by a replicative polymerase if the TLS is error-free, as in the case of Pol η, yet if TLS results in a mismatch, a specialized polymerase is needed to extend it; Pol ζ. Pol ζ is unique in that it can extend terminal mismatches, whereas more processive polymerases cannot. So when a lesion is encountered, the replication fork will stall, PCNA will switch from a processive polymerase to a TLS polymerase such as Pol ι to fix the lesion, then PCNA may switch to Pol ζ to extend the mismatch, and last PCNA will switch to the processive polymerase to continue replication.
Global response to DNA damage
Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA lesions and double-strand breaks. Moreover, DNA damaging agents can damage other biomolecules such as proteins, carbohydrates, lipids, and RNA. The accumulation of damage, to be specific, double-strand breaks or adducts stalling the replication forks, are among known stimulation signals for a global response to DNA damage. The global response to damage is an act directed toward the cells' own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance, or 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 kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure, whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified. These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.
DNA damage checkpoint is a signal transduction pathway that blocks cell cycle progression in G1, G2 and metaphase and slows down the rate of S phase progression when DNA is damaged. It leads to a pause in cell cycle allowing the cell time to repair the damage before continuing to divide.
Checkpoint Proteins can be separated into four groups: phosphatidylinositol 3-kinase (PI3K)-like protein kinase, proliferating cell nuclear antigen (PCNA)-like group, two serine/threonine(S/T) kinases and their adaptors. Central to all DNA damage induced checkpoints responses is a pair of large protein kinases belonging to the first group of PI3K-like protein kinases-the ATM (Ataxia telangiectasia mutated) and ATR (Ataxia- and Rad-related) kinases, whose sequence and functions have been well conserved in evolution. All DNA damage response requires either ATM or ATR because they have the ability to bind to the chromosomes at the site of DNA damage, together with accessory proteins that are platforms on which DNA damage response components and DNA repair complexes can be assembled.
An important downstream target of ATM and ATR is p53, as it is required for inducing apoptosis following DNA damage. The cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and p53-independent mechanisms and can arrest the cell cycle at the G1/S and G2/M checkpoints by deactivating cyclin/cyclin-dependent kinase complexes.
The prokaryotic SOS response
The SOS response is the changes in gene expression in Escherichia coli and other bacteria in response to extensive DNA damage. The prokaryotic SOS system is regulated by two key proteins: LexA and RecA. The LexA homodimer is a transcriptional repressor that binds to operator sequences commonly referred to as SOS boxes. In Escherichia coli it is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes. The SOS response is known to be widespread in the Bacteria domain, but it is mostly absent in some bacterial phyla, like the Spirochetes. The most common cellular signals activating the SOS response are regions of single-stranded DNA (ssDNA), arising from stalled replication forks or double-strand breaks, which are processed by DNA helicase to separate the two DNA strands. In the initiation step, RecA protein binds to ssDNA in an ATP hydrolysis driven reaction creating RecA–ssDNA filaments. RecA–ssDNA filaments activate LexA autoprotease activity, which ultimately leads to cleavage of LexA dimer and subsequent LexA degradation. The loss of LexA repressor induces transcription of the SOS genes and allows for further signal induction, inhibition of cell division and an increase in levels of proteins responsible for damage processing.
In Escherichia coli, SOS boxes are 20-nucleotide long sequences near promoters with palindromic structure and a high degree of sequence conservation. In other classes and phyla, the sequence of SOS boxes varies considerably, with different length and composition, but it is always highly conserved and one of the strongest short signals in the genome. The high information content of SOS boxes permits differential binding of LexA to different promoters and allows for timing of the SOS response. The lesion repair genes are induced at the beginning of SOS response. The error-prone translesion polymerases, for example, UmuCD'2 (also called DNA polymerase V), are induced later on as a last resort. 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 then 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 among different organs that have evolved different sensitivities to DNA damage.
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. A large 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 that 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.
DNA repair and aging
Pathological effects of poor DNA repair
Experimental animals with genetic deficiencies in DNA repair often show decreased life span 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, as a consequence, have shorter lifespans than wild-type mice. In similar manner, 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 life span 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.
Longevity and caloric restriction
A number of individual genes have been identified as influencing variations in life span within a population of organisms. The effects of these genes is strongly dependent on the environment, in particular, 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 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. 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.
It is interesting to note that the C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended life span 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, while not manifesting all the symptoms of old age.
DNA repair and cancer
Because of inherent limitations in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer. There are at least 34 Inherited human DNA repair gene mutations that increase cancer risk. Many of these mutations cause DNA repair to be less effective than normal. In particular, Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. BRCA1 and BRCA2, two famous genes whose mutations confer 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 progenitor cells in the gut, skin, and hematopoietic system 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).
Epigenetic DNA repair defects in cancer
Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumour-suppressor genes and oncogenes, and chromosomal aberrations. However, it has become apparent that cancer is also driven by epigenetic alterations.
Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation) and histone modification, changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1) and changes caused by microRNAs. Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes usually remain through cell divisions, last for multiple cell generations, and can be considered to be epimutations (equivalent to mutations).
While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, appear to be particularly important. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.
Reduced expression of DNA repair genes causes deficient DNA repair. When DNA repair is deficient DNA damages remain in cells at a higher than usual level and these excess damages cause increased frequencies of mutation or epimutation. Mutation rates increase substantially in cells defective in DNA mismatch repair or in homologous recombinational repair (HRR). Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.
Higher levels of DNA damage not only cause increased mutation, but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.
Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations). However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.
Frequencies of epimutations in DNA repair genes
Deficiencies in DNA repair enzymes are occasionally caused by a newly arising somatic mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. For example, when 113 colorectal cancers were examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration). Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.
Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1). In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.
In further examples (tabulated in Cancer epigenetics), epigenetic defects were found at frequencies of between 13%-100% for the DNA repair genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM. These epigenetic defects occurred in various cancers (e.g. breast, ovarian, colorectal and head and neck). Two or three deficiencies in the expression of ERCC1, XPF or PMS2 occur simultaneously in the majority of the 49 colon cancers evaluated by Facista et al.
The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes. Of these, 83 are directly employed in the 5 types of DNA repair processes illustrated in the chart. The more well studied genes central to these repair processes are also shown in the chart. As indicated by the DNA repair genes shown in red, many of the genes in these repair pathways are regulated by epigenetic mechanisms, and these are frequently reduced or silent in various cancers (marked by an asterisk). Two review articles, and two broad experimental survey articles document most of these epigenetic DNA repair deficiencies.
It appears that epigenetic repression of DNA repair genes in accurate DNA repair pathways are central to carcinogenesis. However microhomology-mediated end joining (MMEJ) is an additional error-prone repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5 - 25 complementary base pairs on both strands is identified and used as a basis to align the strands, but with mismatched ends. MMEJ removes extra nucleotides (flaps) where strands are joined, then ligates the strands to create an intact DNA double helix. MMEJ always involves at least a small deletion, so that it is a mutagenic pathway. FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreatic, and lung. Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are shown in cyan (blue) in the chart in this section.
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. 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-cell 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.
Rate of evolutionary change
On some occasions, DNA damage is not repaired, or is repaired by an error-prone mechanism that 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, in a particular gene) is a function of the rate of mutation. As a consequence, the rate and accuracy of DNA repair mechanisms have an influence over the process of evolutionary change. Since the normal adaptation of populations of organisms to changing circumstances (for instance the adaptation of the beaks of a population of finches to the changing presence of hard seeds or insects) proceeds by gene regulation and the recombination and selection of gene variations – alleles – and not by passing on irreparable DNA damages to the offspring, DNA damage protection and repair does not influence the rate of adaptation by gene regulation and by recombination and selection of alleles. On the other hand, DNA damage repair and protection does influence the rate of accumulation of irreparable, advantageous, code expanding, inheritable mutations, and slows down the evolutionary mechanism for expansion of the genome of organisms with new functionalities. The tension between evolvability and mutation repair and protection needs further investigation.
DNA repair technology
A technology named clustered regularly interspaced short palindromic repeat shortened to CRISPR-Cas9 was discovered in 2012. The new technology allows anyone with molecular biology training to alter the genes of any species with precision.
- Accelerated aging disease
- Aging DNA
- Cell cycle
- DNA damage (naturally occurring)
- DNA damage theory of aging
- DNA replication
- Direct DNA damage
- Gene therapy
- Human mitochondrial genetics
- Indirect DNA damage
- Life extension
- The scientific journal DNA Repair under Mutation Research
- Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). Molecular Biology of the Cell, p963. WH Freeman: New York, NY. 5th ed.
- Acharya, PV (1971). "The isolation and partial characterization of age-correlated oligo-deoxyribo-ribonucleotides with covalently linked aspartyl-glutamyl polypeptides.". Johns Hopkins medical journal. Supplement (1): 254–60. PMID 5055816.
- Bjorksten, J; Acharya, PV; Ashman, S; Wetlaufer, DB (1971). "Gerogenic fractions in the tritiated rat.". Journal of the American Geriatrics Society 19 (7): 561–74. doi:10.1111/j.1532-5415.1971.tb02577.x. PMID 5106728.
- Browner, WS; Kahn, AJ; Ziv, E; Reiner, AP; Oshima, J; Cawthon, RM; Hsueh, WC; Cummings, SR. (2004). "The genetics of human longevity". Am J Med 117 (11): 851–60. doi:10.1016/j.amjmed.2004.06.033. PMID 15589490.
- Broad, William J. (7 October 2015). "Nobel Prize in Chemistry Awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar for DNA Studies". New York Times. Retrieved 7 October 2015.
- Staff (7 October 2015). "THE NOBEL PRIZE IN CHEMISTRY 2015 - DNA repair – providing chemical stability for life" (PDF). Nobel Prize. Retrieved 7 October 2015.
- Roulston A, Marcellus RC, Branton PE (1999). "Viruses and apoptosis". Annu. Rev. Microbiol. 53: 577–628. doi:10.1146/annurev.micro.53.1.577. PMID 10547702.
- Madigan MT, Martino JM (2006). Brock Biology of Microorganisms (11th ed.). Pearson. p. 136. ISBN 0-13-196893-9.
- Ohta, Toshihiro; Shin-ichi, Tokishita; Mochizuki, Kayo; Kawase, Jun; Sakahira, Masahide; Yamagata, Hideo (2006). "UV Sensitivity and Mutagenesis of the Extremely Thermophilic Eubacterium Thermus thermophilus HB27". Genes and Environment 28 (2): 56–61. doi:10.3123/jemsge.28.56.
- Braig, M; Schmitt, CA. (2006). "Oncogene-induced senescence: putting the brakes on tumor development". Cancer Res 66 (6): 2881–2884. doi:10.1158/0008-5472.CAN-05-4006. PMID 16540631.
- Lynch, MD. (2006). "How does cellular senescence prevent cancer?". DNA Cell Biol 25 (2): 69–78. doi:10.1089/dna.2006.25.69. PMID 16460230.
- Campisi J, d'Adda di Fagagna F (2007). "Cellular senescence: when bad things happen to good cells.". Rev Mol Cell Biol. 8 (9): 729–40. doi:10.1038/nrm2233. PMID 17667954.
- Best, Benjamin P (2009). "Nuclear DNA damage as a direct cause of aging" (PDF). Rejuvenation Research 12 (3): 199–208. doi:10.1089/rej.2009.0847. PMID 19594328.
- Sancar, A. (2003). "Structure and function of DNA photolyase and cryptochrome blue-light photoreceptors". Chem Rev 103 (6): 2203–37. doi:10.1021/cr0204348. PMID 12797829.
- Michael Lynch, José Ignacio Lucas-Lledó; Lynch, M. (19 February 2009). "Evolution of Mutation Rates: Phylogenomic Analysis of the Photolyase/Cryptochrome Family". Molecular Biology and Evolution 26 (5): 1143–1153. doi:10.1093/molbev/msp029. PMC 2668831. PMID 19228922.
- Watson JD, Baker TA, Bell SP, Gann A, Levine M, Losick R. (2004). Molecular Biology of the Gene. Pearson Benjamin Cummings; CSHL Press. 5th ed., chapters 9 and 10
- Volkert MR (1988). "Adaptive response of Escherichia coli to alkylation damage". Environmental and Molecular Mutagenesis 11 (2): 241–55. doi:10.1002/em.2850110210. PMID 3278898.
- Willey, J; Sherwood, L; Woolverton, C (2014). Prescott’s Microbiology. New York, New York: McGraw Hill. p. 381. ISBN 978-0-07-3402-40-6.
- Reardon, J; Sancar, A (2006). "Purification and Characterization of Escherichia coli and Human Nucleotide Excision Repair Enzyme Systems". Methods in Enzymology 408: 189–213. doi:10.1016/S0076-6879(06)08012-8. PMID 16793370.
- Berg, M; Tymoczko, J; Stryer, L (2012). Biochemistry 7th edition. New York: W.H. Freeman and Company. p. 840. ISBN 9781429229364.
- Wilson TE, Grawunder U, Lieber MR (July 1997). "Yeast DNA ligase IV mediates non-homologous DNA end joining". Nature 388 (6641): 495–8. doi:10.1038/41365. PMID 9242411.
- Moore JK, Haber JE (May 1996). "Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae". Molecular and Cellular Biology 16 (5): 2164–73. PMC 231204. PMID 8628283.
- Boulton SJ, Jackson SP (September 1996). "Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways". The EMBO Journal 15 (18): 5093–103. PMC 452249. PMID 8890183.
- Wilson TE, Lieber MR (August 1999). "Efficient processing of DNA ends during yeast nonhomologous end joining. Evidence for a DNA polymerase beta (Pol4)-dependent pathway". The Journal of Biological Chemistry 274 (33): 23599–609. doi:10.1074/jbc.274.33.23599. PMID 10438542.
- Budman J, Chu G (February 2005). "Processing of DNA for nonhomologous end-joining by cell-free extract". The EMBO Journal 24 (4): 849–60. doi:10.1038/sj.emboj.7600563. PMC 549622. PMID 15692565.
- Wang H, Perrault AR, Takeda Y, Qin W, Wang H, Iliakis G (September 2003). "Biochemical evidence for Ku-independent backup pathways of NHEJ". Nucleic Acids Research 31 (18): 5377–88. doi:10.1093/nar/gkg728. PMC 203313. PMID 12954774.
- Jung D, Alt FW (January 2004). "Unraveling V(D)J recombination; insights into gene regulation". Cell 116 (2): 299–311. doi:10.1016/S0092-8674(04)00039-X. PMID 14744439.
- Truong LN, Li Y, Shi LZ, Hwang PY, He J, Wang H, Razavian N, Berns MW, Wu X (2013). "Microhomology-mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells". Proc. Natl. Acad. Sci. U.S.A. 110 (19): 7720–5. doi:10.1073/pnas.1213431110. PMC 3651503. PMID 23610439.
- Sharma S, Javadekar SM, Pandey M, Srivastava M, Kumari R, Raghavan SC (2015). "Homology and enzymatic requirements of microhomology-dependent alternative end joining". Cell Death Dis 6: e1697. doi:10.1038/cddis.2015.58. PMC 4385936. PMID 25789972.
- Liang L, Deng L, Chen Y, Li GC, Shao C, Tischfield JA (2005). "Modulation of DNA end joining by nuclear proteins". J. Biol. Chem. 280 (36): 31442–9. doi:10.1074/jbc.M503776200. PMID 16012167.
- Decottignies A (2013). "Alternative end-joining mechanisms: a historical perspective". Front Genet 4: 48. doi:10.3389/fgene.2013.00048. PMC 3613618. PMID 23565119.
- Zahradka K, Slade D, Bailone A, et al. (October 2006). "Reassembly of shattered chromosomes in Deinococcus radiodurans". Nature 443 (7111): 569–73. doi:10.1038/nature05160. PMID 17006450.
- Waters LS, Minesinger BK, Wiltrout ME, D'Souza S, Woodruff RV, Walker GC (March 2009). "Eukaryotic Translesion Polymerases and Their Roles and Regulation in DNA Damage Tolerance". Microbiol. Mol. Biol. Rev. 73 (1): 134–54. doi:10.1128/MMBR.00034-08. PMC 2650891. PMID 19258535.
- LC Colis; P Raychaudhury; AK Basu (2008). "Mutational specificity of gamma-radiation-induced guanine-thymine and thymine-guanine intrastrand cross-links in mammalian cells and translesion synthesis past the guanine-thymine lesion by human DNA polymerase eta". Biochemistry 47 (6): 8070–8079. doi:10.1021/bi800529f. PMID 18616294.
- P Raychaudhury; Basu, Ashis K. (2011). "Genetic requirement for mutagenesis of the G[8,5-Me]T cross-link in Escherichia coli: DNA polymerases IV and V compete for error-prone bypass". Biochemistry 50 (12): 2330–2338. doi:10.1021/bi102064z. PMID 21302943.
- "Translesion Synthesis". Research.chem.psu.edu. Retrieved 2012-08-14.
- Wang, Z (2001). "Translesion synthesis by the UmuC family of DNA polymerases". Mutat. Res. 486 (2): 59–70. doi:10.1016/S0921-8777(01)00089-1. PMID 11425512.
- Friedberg EC, Walker GC, Siede W, Wood RD, Schultz RA, Ellenberger T. (2006). DNA Repair and Mutagenesis, part 3. ASM Press. 2nd ed.
- Bakkenist CJ, Kastan MB (January 2003). "DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation". Nature 421 (6922): 499–506. doi:10.1038/nature01368. PMID 12556884.
- Wei, Qingyi; Lei Li; David Chen (2007). DNA Repair, Genetic Instability, and Cancer. World Scientific. ISBN 981-270-014-5.[page needed]
- Schonthal, Axel H. (2004). Checkpoint Controls and Cancer. Humana Press. ISBN 1-58829-500-1.[page needed]
- Gartel AL, Tyner AL (June 2002). "The role of the cyclin-dependent kinase inhibitor p21 in apoptosis". Molecular Cancer Therapeutics 1 (8): 639–49. PMID 12479224.
- Janion, C. (2001). "Some aspects of the SOS response system-a critical survey". Acta Biochim Pol. 48 (3): 599–610. PMID 11833768.
- Erill, I; Campoy, S; Barbé, J (2007). "Aeons of distress: an evolutionary perspective on the bacterial SOS response". FEMS Microbiol Rev. 31 (6): 637–656. doi:10.1111/j.1574-6976.2007.00082.x. PMID 17883408.
- Schlacher, K; Pham, P; Cox, MM; Goodman, MF. (2006). "Roles of DNA Polymerase V and RecA Protein in SOS Damage-Induced Mutation". Chem. Rev 106 (2): 406–419. doi:10.1021/cr0404951. PMID 16464012.
- Fry, RC; Begley, TJ; Samson, LD (2004). "Genome-wide responses to DNA-damaging agents". Annu Rev Microbiol 59: 357–77. doi:10.1146/annurev.micro.59.031805.133658. PMID 16153173.
- Espejel, S; Martin, M; Klatt, P; Martin-Caballero, J; Flores, JM; Blasco, MA. (2004). "Shorter telomeres, accelerated ageing and increased lymphoma in DNA-PKcs-deficient mice". EMBO Rep 5 (5): 503–9. doi:10.1038/sj.embor.7400127. PMC 1299048. PMID 15105825.
- De Boer, J; Andressoo, JO; De Wit, J; Huijmans, J; Beems, RB; Van Steeg, H; Weeda, G; Van Der Horst, GT; et al. (2002). "Premature aging in mice deficient in DNA repair and transcription". Science 296 (5571): 1276–9. doi:10.1126/science.1070174. PMID 11950998.
- Dolle, ME; Busuttil, RA; Garcia, AM; Wijnhoven, S; van Drunen, E; Niedernhofer, LJ; der Horst, G; Hoeijmakers, JH; et al. (2006). "Increased genomic instability is not a prerequisite for shortened life span in DNA repair deficient mice". Mutation Research 596 (1–2): 22–35. doi:10.1016/j.mrfmmm.2005.11.008. PMID 16472827.
- Kobayashi, Y; Narumi, I; Satoh, K; Funayama, T; Kikuchi, M; Kitayama, S; Watanabe, H. (2004). "Radiation response mechanisms of the extremely radioresistant bacterium Deinococcus radiodurans". Biol Sci Space 18 (3): 134–5. PMID 15858357.
- Spindler, SR. (2005). "Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction". Mech Ageing Dev 126 (9): 960–6. doi:10.1016/j.mad.2005.03.016. PMID 15927235.
- Tissenbaum, HA; Guarente, L. (2001). "Increased dosage of a sir-2 gene extends life span in Caenorhabditis elegans". Nature 410 (6825): 227–30. doi:10.1038/35065638. PMID 11242085.
- Cohen, HY; Miller, C; Bitterman, KJ; Wall, NR; Hekking, B; Kessler, B; Howitz, KT; Gorospe, M; et al. (2004). "Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase". Science 305 (5682): 390–2. doi:10.1126/science.1099196. PMID 15205477.
- Cabelof, DC; Yanamadala, S; Raffoul, JJ; Guo, Z; Soofi, A; Heydari, AR. (2003). "Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline". DNA Repair (Amst.) 2 (3): 295–307. doi:10.1016/S1568-7864(02)00219-7. PMID 12547392.
- Stuart, JA; Karahalil, B; Hogue, BA; Souza-Pinto, NC; Bohr, VA. (2004). "Mitochondrial and nuclear DNA base excision repair are affected differently by caloric restriction". FASEB J 18 (3): 595–7. doi:10.1096/fj.03-0890fje. PMID 14734635.
- Walker, DW; McColl, G; Jenkins, NL; Harris, J; Lithgow, GJ. (2000). "Evolution of lifespan in C. elegans". Nature 405 (6784): 296–7. doi:10.1038/35012693. PMID 10830948.
- Johnson, George (28 December 2010). "Unearthing Prehistoric Tumors, and Debate". The New York Times.
If we lived long enough, sooner or later we all would get cancer.
- Alberts, B; Johnson A; Lewis J; et al. (2002). "The Preventable Causes of Cancer". Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-4072-9.
A certain irreducible background incidence of cancer is to be expected regardless of circumstances: mutations can never be absolutely avoided, because they are an inescapable consequence of fundamental limitations on the accuracy of DNA replication, as discussed in Chapter 5. If a human could live long enough, it is inevitable that at least one of his or her cells would eventually accumulate a set of mutations sufficient for cancer to develop.
- Baylin SB; Ohm, Joyce E. (February 2006). "Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction?". Nat. Rev. Cancer 6 (2): 107–16. doi:10.1038/nrc1799. PMID 16491070.
- Kanwal R, Gupta S (April 2012). "Epigenetic modifications in cancer". Clinical Genetics 81 (4): 303–11. doi:10.1111/j.1399-0004.2011.01809.x. PMC 3590802. PMID 22082348.
- Baldassarre G, Battista S, Belletti B, et al. (April 2003). "Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma". Molecular and Cellular Biology 23 (7): 2225–38. doi:10.1128/MCB.23.7.2225-2238.2003. PMC 150734. PMID 12640109.
- Jacinto FV, Esteller M; Esteller, M. (July 2007). "Mutator pathways unleashed by epigenetic silencing in human cancer". Mutagenesis 22 (4): 247–53. doi:10.1093/mutage/gem009. PMID 17412712.
- Lahtz C; Pfeifer, G. P. (February 2011). "Epigenetic changes of DNA repair genes in cancer". J Mol Cell Biol 3 (1): 51–8. doi:10.1093/jmcb/mjq053. PMC 3030973. PMID 21278452. http://jmcb.oxfordjournals.org/content/3/1/51.long
- Bernstein C, Nfonsam V, Prasad AR, Bernstein H (March 2013). "Epigenetic field defects in progression to cancer". World J Gastrointest Oncol 5 (3): 43–9. doi:10.4251/wjgo.v5.i3.43. PMC 3648662. PMID 23671730.
- Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). "Chapter 16: DNA Damage, DNA Repair and Cancer", New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech.
- Narayanan L, Fritzell JA, Baker SM, Liskay RM, Glazer PM (April 1997). "Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2". Proceedings of the National Academy of Sciences of the United States of America 94 (7): 3122–7. doi:10.1073/pnas.94.7.3122. PMC 20332. PMID 9096356.
- Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM (December 2006). "Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6". Carcinogenesis 27 (12): 2402–8. doi:10.1093/carcin/bgl079. PMC 2612936. PMID 16728433.
- Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A (March 2002). "Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation". EMBO Reports 3 (3): 255–60. doi:10.1093/embo-reports/kvf037. PMC 1084010. PMID 11850397.
- German J (March 1969). "Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients". American Journal of Human Genetics 21 (2): 196–227. PMC 1706430. PMID 5770175.
- O'Hagan HM, Mohammad HP, Baylin SB (2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLoS Genetics 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159.
- Cuozzo C, Porcellini A, Angrisano T, et al. (July 2007). "DNA damage, homology-directed repair, and DNA methylation". PLoS Genetics 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978.
- Malkin D (April 2011). "Li-fraumeni syndrome". Genes & Cancer 2 (4): 475–84. doi:10.1177/1947601911413466. PMC 3135649. PMID 21779515.
- Fearon ER (November 1997). "Human cancer syndromes: clues to the origin and nature of cancer". Science 278 (5340): 1043–50. doi:10.1126/science.278.5340.1043. PMID 9353177.
- Halford S, Rowan A, Sawyer E, Talbot I, Tomlinson I (June 2005). "O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions". Gut 54 (6): 797–802. doi:10.1136/gut.2004.059535. PMC 1774551. PMID 15888787.
- Shen L, Kondo Y, Rosner GL, et al. (September 2005). "MGMT promoter methylation and field defect in sporadic colorectal cancer". Journal of the National Cancer Institute 97 (18): 1330–8. doi:10.1093/jnci/dji275. PMID 16174854.
- Psofaki V, Kalogera C, Tzambouras N, et al. (July 2010). "Promoter methylation status of hMLH1, MGMT, and CDKN2A/p16 in colorectal adenomas". World Journal of Gastroenterology 16 (28): 3553–60. doi:10.3748/wjg.v16.i28.3553. PMC 2909555. PMID 20653064.
- Lee KH, Lee JS, Nam JH, et al. (October 2011). "Promoter methylation status of hMLH1, hMSH2, and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence". Langenbeck's Archives of Surgery 396 (7): 1017–26. doi:10.1007/s00423-011-0812-9. PMID 21706233.
- Amatu A, Sartore-Bianchi A, Moutinho C, et al. (April 2013). "Promoter CpG island hypermethylation of the DNA repair enzyme MGMT predicts clinical response to dacarbazine in a phase II study for metastatic colorectal cancer". Clinical Cancer Research 19 (8): 2265–72. doi:10.1158/1078-0432.CCR-12-3518. PMID 23422094.
- Mokarram P, Zamani M, Kavousipour S, et al. (May 2013). "Different patterns of DNA methylation of the two distinct O6-methylguanine-DNA methyltransferase (O6-MGMT) promoter regions in colorectal cancer". Molecular Biology Reports 40 (5): 3851–7. doi:10.1007/s11033-012-2465-3. PMID 23271133.
- Truninger K, Menigatti M, Luz J, et al. (May 2005). "Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer". Gastroenterology 128 (5): 1160–71. doi:10.1053/j.gastro.2005.01.056. PMID 15887099.
- Valeri N, Gasparini P, Fabbri M, et al. (April 2010). "Modulation of mismatch repair and genomic stability by miR-155". Proceedings of the National Academy of Sciences of the United States of America 107 (15): 6982–7. doi:10.1073/pnas.1002472107. PMC 2872463. PMID 20351277.
- Facista A, Nguyen H, Lewis C, et al. (2012). "Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer". Genome Integrity 3 (1): 3. doi:10.1186/2041-9414-3-3. PMC 3351028. PMID 22494821.
- Human DNA Repair Genes, 15 April 2014, MD Anderson Cancer Center, University of Texas
- Xinrong Chen and Tao Chen (2011). "Chapter 18: Roles of MicroRNA in DNA Damage and Repair", DNA Repair, Dr. Inna Kruman (Ed.), ISBN 978-953-307-697-3, InTech.
- Krishnan K, Steptoe AL, Martin HC, et al. (February 2013). "MicroRNA-182-5p targets a network of genes involved in DNA repair". RNA 19 (2): 230–42. doi:10.1261/rna.034926.112. PMC 3543090. PMID 23249749.
- Chaisaingmongkol J, Popanda O, Warta R, et al. (December 2012). "Epigenetic screen of human DNA repair genes identifies aberrant promoter methylation of NEIL1 in head and neck squamous cell carcinoma". Oncogene 31 (49): 5108–16. doi:10.1038/onc.2011.660. PMID 22286769.
- Singh P, Yang M, Dai H, Yu D, Huang Q, Tan W, Kernstine KH, Lin D, Shen B (2008). "Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers". Mol. Cancer Res. 6 (11): 1710–7. doi:10.1158/1541-7786.MCR-08-0269. PMC 2948671. PMID 19010819.
- Lam JS, Seligson DB, Yu H, Li A, Eeva M, Pantuck AJ, Zeng G, Horvath S, Belldegrun AS (2006). "Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score". BJU Int. 98 (2): 445–51. doi:10.1111/j.1464-410X.2006.06224.x. PMID 16879693.
- Kim JM, Sohn HY, Yoon SY, Oh JH, Yang JO, Kim JH, Song KS, Rho SM, Yoo HS, Yoo HS, Kim YS, Kim JG, Kim NS (2005). "Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells". Clin. Cancer Res. 11 (2 Pt 1): 473–82. PMID 15701830.
- Wang K, Xie C, Chen D (2014). "Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis". Int. J. Mol. Med. 33 (5): 1268–74. doi:10.3892/ijmm.2014.1682. PMID 24590400.
- Krause A, Combaret V, Iacono I, Lacroix B, Compagnon C, Bergeron C, Valsesia-Wittmann S, Leissner P, Mougin B, Puisieux A (2005). "Genome-wide analysis of gene expression in neuroblastomas detected by mass screening". Cancer Lett. 225 (1): 111–20. doi:10.1016/j.canlet.2004.10.035. PMID 15922863.
- Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C, Walter K, Sato N, Parker A, Ashfaq R, Jaffee E, Ryu B, Jones J, Eshleman JR, Yeo CJ, Cameron JL, Kern SE, Hruban RH, Brown PO, Goggins M (2003). "Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays". Am. J. Pathol. 162 (4): 1151–62. doi:10.1016/S0002-9440(10)63911-9. PMC 1851213. PMID 12651607.
- Sato M, Girard L, Sekine I, Sunaga N, Ramirez RD, Kamibayashi C, Minna JD (2003). "Increased expression and no mutation of the Flap endonuclease (FEN1) gene in human lung cancer". Oncogene 22 (46): 7243–6. doi:10.1038/sj.onc.1206977. PMID 14562054.
- Cromie, GA; Connelly, JC; Leach, DR (2001). "Recombination at double-strand breaks and DNA ends: conserved mechanisms from phage to humans". Mol Cell. 8 (6): 1163–74. doi:10.1016/S1097-2765(01)00419-1. PMID 11779493.
- O'Brien, PJ. (2006). "Catalytic promiscuity and the divergent evolution of DNA repair enzymes". Chem Rev 106 (2): 720–52. doi:10.1021/cr040481v. PMID 16464022.
- Maresca, B; Schwartz, JH (2006). "Sudden origins: a general mechanism of evolution based on stress protein concentration and rapid environmental change". Anat Rec B New Anat 289 (1): 38–46. doi:10.1002/ar.b.20089. PMID 16437551.
- DeJong W, Degens H (2011). "The Evolutionary Dynamics of Digital and Nucleotide Codes: A Mutation Protection Perspective" (PDF). Open Evolution Journal, 5: 1-4.
- "CRISPR gene-editing tool has scientists thrilled — but nervous" CBC news. Author Kelly Crowe. November 30, 2015.
|Library resources about
- Roswell Park Cancer Institute DNA Repair Lectures
- A comprehensive list of Human DNA Repair Genes
- 3D structures of some DNA repair enzymes
- Human DNA repair diseases
- DNA repair special interest group
- DNA Repair
- DNA Damage and DNA Repair
- Segmental Progeria
- DNA-damage repair; the good, the bad, and the ugly