Cell damage

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Cell damage (also known as cell injury) is a variety of changes of stress that a cell suffers due to external as well as internal environmental changes. Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. Cell damage can be reversible or irreversible. Depending on the extent of injury, the cellular response may be adaptive and where possible, homeostasis is restored. [1] Cell death occurs when the severity of the injury exceeds the cell's ability to repair itself. [2] Cell death is relative to both the length of exposure to a harmful stimulus and the severity of the damage caused. [1] Cell death may occur by necrosis or apoptosis.

Contents

Causes

Targets

The most notable components of the cell that are targets of cell damage are the DNA and the cell membrane.

Types of damage

Some cell damage can be reversed once the stress is removed or if compensatory cellular changes occur. Full function may return to cells but in some cases, a degree of injury will remain. [6]

Reversible

Cellular swelling

Cellular swelling (or cloudy swelling) may occur due to cellular hypoxia, which damages the sodium-potassium membrane pump; it is reversible when the cause is eliminated. [7] Cellular swelling is the first manifestation of almost all forms of injury to cells. When it affects many cells in an organ, it causes some pallor, increased turgor, and increase in weight of the organ. On microscopic examination, small clear vacuoles may be seen within the cytoplasm; these represent distended and pinched-off segments of the endoplasmic reticulum. This pattern of non-lethal injury is sometimes called hydropic change or vacuolar degeneration. [8] Hydropic degeneration is a severe form of cloudy swelling. It occurs with hypokalemia due to vomiting or diarrhea.

The ultrastructural changes of reversible cell injury include:

  • Blebbing
  • Blunting
  • distortion of microvilli
  • loosening of intercellular attachments
  • mitochondrial changes
  • dilation of the endoplasmic reticulum

Fatty change

In fatty change, the cell has been damaged and is unable to adequately metabolize fat. Small vacuoles of fat accumulate and become dispersed within cytoplasm. Mild fatty change may have no effect on cell function; however, more severe fatty change can impair cellular function. In the liver, the enlargement of hepatocytes due to fatty change may compress adjacent bile canaliculi, leading to cholestasis. Depending on the cause and severity of the lipid accumulation, fatty change is generally reversible. Fatty change is also known as fatty degeneration, fatty metamorphosis, or fatty steatosis.

Irreversible

Necrosis

Necrosis is characterised by cytoplasmic swelling, irreversible damage to the plasma membrane, and organelle breakdown leading to cell death. [9] The stages of cellular necrosis include pyknosis; clumping of chromosomes and shrinking of the nucleus of the cell, karyorrhexis; fragmentation of the nucleus and break up of the chromatin into unstructured granules, and karyolysis; dissolution of the cell nucleus. [10] Cytosolic components that leak through the damaged plasma membrane into the extracellular space can incur an inflammatory response. [11]

There are six types of necrosis: [12]

  • Coagulative necrosis
  • Liquefactive necrosis
  • Caseous necrosis
  • Fat necrosis
  • Fibroid necrosis
  • Gangrenous necrosis

Apoptosis

Apoptosis is the programmed cell death of superfluous or potentially harmful cells in the body. It is an energy-dependent process mediated by proteolytic enzymes called caspases, which trigger cell death through the cleaving of specific proteins in the cytoplasm and nucleus. [13] The dying cells shrink and condense into apoptotic bodies. The cell surface is altered so as to display properties that lead to rapid phagocytosis by macrophages or neighbouring cells. [13] Unlike necrotic cell death, Neighbouring cells are not damaged by apoptosis as cytosolic products are safely isolated by membranes prior to undergoing phagocytosis. [11] It is considered an important component of various bioprocesses including cell turnover, hormone-dependent atrophy, proper development and functioning of the immune and embryonic system, it also helps in chemical-induced cell death which is genetically mediated. [14] There is some evidence that certain symptoms of "apoptosis" such as endonuclease activation can be spuriously induced without engaging a genetic cascade. It is also becoming clear that mitosis and apoptosis are toggled or linked in some way and that the balance achieved depends on signals received from appropriate growth or survival factors. There are research being conducted to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that controls cell cycle arrest and apoptosis. [15] In the average adult between 50 and 70 billion cells die each day due to apoptosis. Inhibition of apoptosis can result in a number of cancers, autoimmune diseases, inflammatory diseases, and viral infections. Hyperactive apoptosis can lead to neurodegenerative diseases, hematologic diseases, and tissue damage.

Repair

When a cell is damaged, the body will try to repair or replace the cell to continue normal functions. If a cell dies, the body will remove it and replace it with another functioning cell, or fill the gap with connective tissue to provide structural support for the remaining cells. The motto of the repair process is to fill a gap caused by the damaged cells to regain structural continuity. Normal cells try to regenerate the damaged cells but this cannot always happen.

Regeneration

Regeneration of parenchyma cells, or the functional cells, of an organism. The body can make more cells to replace the damaged cells keeping the organ or tissue intact and fully functional.

Replacement

When a cell cannot be regenerated, the body will replace it with stromal connective tissue to maintain tissue or organ function. Stromal cells are the cells that support the parenchymal cells in any organ. Fibroblasts, immune cells, pericytes, and inflammatory cells are the most common types of stromal cells. [16]

Biochemical changes in cellular injury

ATP (adenosine triphosphate) depletion is a common biological alteration that occurs with cellular injury. This change can happen despite the inciting agent of the cell damage. A reduction in intracellular ATP can have a number of functional and morphologic consequences during cell injury. These effects include:

DNA damage and repair

DNA damage

DNA damage (or RNA damage in the case of some virus genomes) appears to be a fundamental problem for life. As noted by Haynes, [18] the subunits of DNA are not endowed with any peculiar kind of quantum mechanical stability, and thus DNA is vulnerable to all the "chemical horrors" that might befall any such molecule in a warm aqueous medium. These chemical horrors are DNA damages that include various types of modification of the DNA bases, single- and double-strand breaks, and inter-strand cross-links (see DNA damage (naturally occurring). DNA damages are distinct from mutations although both are errors in the DNA. Whereas DNA damages are abnormal chemical and structural alterations, mutations ordinarily involve the normal four bases in new arrangements. Mutations can be replicated, and thus inherited when the DNA replicates. In contrast, DNA damages are altered structures that cannot, themselves, be replicated.

Several different repair processes can remove DNA damages (see chart in DNA repair). However, those DNA damages that remain un-repaired can have detrimental consequences. DNA damages may block replication or gene transcription. These blockages can lead to cell death. In multicellular organisms, cell death in response to DNA damage may occur by a programmed process, apoptosis. [19] Alternatively, when DNA polymerase replicates a template strand containing a damaged site, it may inaccurately bypass the damage and, as a consequence, introduce an incorrect base leading to a mutation. Experimentally, mutation rates increase substantially in cells defective in DNA mismatch repair [20] [21] or in Homologous recombinational repair (HRR). [22]

In both prokaryotes and eukaryotes, DNA genomes are vulnerable to attack by reactive chemicals naturally produced in the intracellular environment and by agents from external sources. An important internal source of DNA damage in both prokaryotes and eukaryotes is reactive oxygen species (ROS) formed as byproducts of normal aerobic metabolism. For eukaryotes, oxidative reactions are a major source of DNA damage (see DNA damage (naturally occurring) and Sedelnikova et al. [23] ). In humans, about 10,000 oxidative DNA damages occur per cell per day. [24] In the rat, which has a higher metabolic rate than humans, about 100,000 oxidative DNA damages occur per cell per day. In aerobically growing bacteria, ROS appear to be a major source of DNA damage, as indicated by the observation that 89% of spontaneously occurring base substitution mutations are caused by introduction of ROS-induced single-strand damages followed by error-prone replication past these damages. [25] Oxidative DNA damages usually involve only one of the DNA strands at any damaged site, but about 1–2% of damages involve both strands. [26] The double-strand damages include double-strand breaks (DSBs) and inter-strand crosslinks. For humans, the estimated average number of endogenous DNA DSBs per cell occurring at each cell generation is about 50. [27] This level of formation of DSBs likely reflects the natural level of damages caused, in large part, by ROS produced by active metabolism.

Repair of DNA damages

Five major pathways are employed in repairing different types of DNA damages. These five pathways are nucleotide excision repair, base excision repair, mismatch repair, non-homologous end-joining and homologous recombinational repair (HRR) (see chart in DNA repair) and reference. [19] Only HRR can accurately repair double-strand damages, such as DSBs. The HRR pathway requires that a second homologous chromosome be available to allow recovery of the information lost by the first chromosome due to the double-strand damage.

DNA damage appears to play a key role in mammalian aging, and an adequate level of DNA repair promotes longevity (see DNA damage theory of aging and reference. [28] ). In addition, an increased incidence of DNA damage and/or reduced DNA repair cause an increased risk of cancer (see Cancer, Carcinogenesis and Neoplasm) and reference [28] ). Furthermore, the ability of HRR to accurately and efficiently repair double-strand DNA damages likely played a key role in the evolution of sexual reproduction (see Evolution of sexual reproduction and reference). [29] In extant eukaryotes, HRR during meiosis provides the major benefit of maintaining fertility. [29]

See also

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, approximately twenty to thirty billion cells die per day.

<span class="mw-page-title-main">Necrosis</span> Unprogrammed cell death caused by external cell injury

Necrosis is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death. While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal.

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

<span class="mw-page-title-main">Genetic recombination</span> Production of offspring with combinations of traits that differ from those found in either parent

Genetic recombination is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryotes, genetic recombination during meiosis can lead to a novel set of genetic information that can be further passed on from parents to offspring. Most recombination occurs naturally and can be classified into two types: (1) interchromosomal recombination, occurring through independent assortment of alleles whose loci are on different but homologous chromosomes ; & (2) intrachromosomal recombination, occurring through crossing over.

<span class="mw-page-title-main">DNA repair</span> Cellular mechanism

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 radiation can cause DNA damage, resulting in tens of thousands of 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. This can eventually lead to malignant tumors, or cancer as per the two hit hypothesis.

RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.

<span class="mw-page-title-main">Cell death</span> Biological cell ceasing to carry out its functions

Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as diseases, localized injury, or the death of the organism of which the cells are part. Apoptosis or Type I cell-death, and autophagy or Type II cell-death are both forms of programmed cell death, while necrosis is a non-physiological process that occurs as a result of infection or injury.

<span class="mw-page-title-main">Germline mutation</span> Inherited genetic variation

A germline mutation, or germinal mutation, is any detectable variation within germ cells. Mutations in these cells are the only mutations that can be passed on to offspring, when either a mutated sperm or oocyte come together to form a zygote. After this fertilization event occurs, germ cells divide rapidly to produce all of the cells in the body, causing this mutation to be present in every somatic and germline cell in the offspring; this is also known as a constitutional mutation. Germline mutation is distinct from somatic mutation.

<span class="mw-page-title-main">Neoplasm</span> Abnormal mass of tissue as a result of abnormal growth or division of cells

A neoplasm is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists in growing abnormally, even if the original trigger is removed. This abnormal growth usually forms a mass, when it may be called a tumour or tumor.

<span class="mw-page-title-main">Spermatocyte</span> Sperm precursor cell that undergoes meiosis

Spermatocytes are a type of male gametocyte in animals. They derive from immature germ cells called spermatogonia. They are found in the testis, in a structure known as the seminiferous tubules. There are two types of spermatocytes, primary and secondary spermatocytes. Primary and secondary spermatocytes are formed through the process of spermatocytogenesis.

<span class="mw-page-title-main">Poly (ADP-ribose) polymerase</span> Family of proteins

Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.

<span class="mw-page-title-main">Ataxia telangiectasia and Rad3 related</span> Protein kinase that detects DNA damage and halts cell division

Serine/threonine-protein kinase ATR also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1) is an enzyme that, in humans, is encoded by the ATR gene. It is a large kinase of about 301.66 kDa. ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family. ATR is activated in response to single strand breaks, and works with ATM to ensure genome integrity.

Caretaker genes encode products that stabilize the genome. Fundamentally, mutations in caretaker genes lead to genomic instability. Tumor cells arise from two distinct classes of genomic instability: mutational instability arising from changes in the nucleotide sequence of DNA and chromosomal instability arising from improper rearrangement of chromosomes.

<span class="mw-page-title-main">ADP/ATP translocase 4</span> Protein-coding gene in the species Homo sapiens

ADP/ATP translocase 4 (ANT4) is an enzyme that in humans is encoded by the SLC25A31 gene on chromosome 4. This enzyme inhibits apoptosis by catalyzing ADP/ATP exchange across the mitochondrial membranes and regulating membrane potential. In particular, ANT4 is essential to spermatogenesis, as it imports ATP into sperm mitochondria to support their development and survival. Outside this role, the SLC25AC31 gene has not been implicated in any human disease.

The DNA damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring DNA damage. Damage in this context is a DNA alteration that has an abnormal structure. Although both mitochondrial and nuclear DNA damage can contribute to aging, nuclear DNA is the main subject of this analysis. Nuclear DNA damage can contribute to aging either indirectly or directly.

Ischemic cell death, or oncosis, is a form of accidental cell death. The process is characterized by an ATP depletion within the cell leading to impairment of ionic pumps, cell swelling, clearing of the cytosol, dilation of the endoplasmic reticulum and golgi apparatus, mitochondrial condensation, chromatin clumping, and cytoplasmic bleb formation. Oncosis refers to a series of cellular reactions following injury that precedes cell death. The process of oncosis is divided into three stages. First, the cell becomes committed to oncosis as a result of damage incurred to the plasma membrane through toxicity or ischemia, resulting in the leak of ions and water due to ATP depletion. The ionic imbalance that occurs subsequently causes the cell to swell without a concurrent change in membrane permeability to reverse the swelling. In stage two, the reversibility threshold for the cell is passed and the cell becomes committed to cell death. During this stage the membrane becomes abnormally permeable to trypan blue and propidium iodide, indicating membrane compromise. The final stage is cell death and removal of the cell via phagocytosis mediated by an inflammatory response.

Genome instability refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.

<span class="mw-page-title-main">Necroptosis</span> Programmed form of necrosis, or inflammatory cell death

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a nucleobase missing from the backbone of DNA, or a chemically changed base such as 8-OHdG. DNA damage can occur naturally or via environmental factors, but is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of base pairs. DNA damages cause changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly. The DNA damage response (DDR) is a complex signal transduction pathway which recognizes when DNA is damaged and initiates the cellular response to the damage.

Parthanatos is a form of programmed cell death that is distinct from other cell death processes such as necrosis and apoptosis. While necrosis is caused by acute cell injury resulting in traumatic cell death and apoptosis is a highly controlled process signalled by apoptotic intracellular signals, parthanatos is caused by the accumulation of Poly(ADP ribose) (PAR) and the nuclear translocation of apoptosis-inducing factor (AIF) from mitochondria. Parthanatos is also known as PARP-1 dependent cell death. PARP-1 mediates parthanatos when it is over-activated in response to extreme genomic stress and synthesizes PAR which causes nuclear translocation of AIF. Parthanatos is involved in diseases that afflict hundreds of millions of people worldwide. Well known diseases involving parthanatos include Parkinson's disease, stroke, heart attack, and diabetes. It also has potential use as a treatment for ameliorating disease and various medical conditions such as diabetes and obesity.

References

  1. 1 2 Wolf, Ronni; et al. (2011). Emergency Dermatology . Cambridge University Press. pp.  1–10. ISBN   9780521717335.
  2. ↑ Cobb, J. P.; et al. (1996). "Mechanisms of cell injury and death". British Journal of Anaesthesia. 77 (1): 3–10. doi: 10.1093/bja/77.1.3 . PMID   8703628.
  3. ↑ Klaassen, C.D., Ed.: Casarett and Doull's Toxicology: The Basic Science of Poisons. Sixth Edition, McGraw-Hill, 2007 [2001].
  4. ↑ Silva Soares C., Carlos. "Causes of Cell Injury" (PDF). is.muni.cz/.
  5. ↑ Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J. (2004). Molecular Biology of the Cell, WH Freeman: New York, NY. 5th ed., p. 963
  6. ↑ "Cell Injury and Death". The Lecturio Medical Concept Library. Retrieved 7 July 2021.
  7. ↑ Hayes, A.W., Ed.: Principles and Methods of Toxicology Fourth Edition, Raven Press, New York, 2001 and 5th edition (2008).
  8. ↑ "Cellular Swelling." Humpath.com-Human Pathology. Humpath.com, 30 Jan 2006. Web. 21 Mar 2013.
  9. ↑ Festjens, Nele; Vanden Berghe, Tom; Vandenabeele, Peter (2006-09-01). "Necrosis, a well-orchestrated form of cell demise: Signalling cascades, important mediators and concomitant immune response". Biochimica et Biophysica Acta (BBA) - Bioenergetics. Mitochondria: from Molecular Insight to Physiology and Pathology. 1757 (9–10): 1371–1387. doi: 10.1016/j.bbabio.2006.06.014 . PMID   16950166.
  10. ↑ "Medical Definition of PYKNOSIS". merriam-webster.com. Retrieved 2016-04-16.
  11. 1 2 Proskuryakov, Sergey Y a; Konoplyannikov, Anatoli G; Gabai, Vladimir L (2003-02-01). "Necrosis: a specific form of programmed cell death?". Experimental Cell Research. 283 (1): 1–16. doi:10.1016/S0014-4827(02)00027-7. PMID   12565815.
  12. ↑ "What Is Necrosis? - Definition & Types - Video & Lesson Transcript | Study.com". Study.com. Retrieved 2016-04-16.
  13. 1 2 Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter (2002-01-01). Molecular Biology of the Cell (4th ed.). Garland Science. ISBN   978-0815332183.
  14. ↑ Elmore, Susan (2007). "Apoptosis: A Review of Programmed Cell Death". Toxicologic Pathology. 35 (4): 495–516. doi:10.1080/01926230701320337. ISSN   0192-6233. PMC   2117903 . PMID   17562483.
  15. ↑ Korashy, H. M.; Maayah, Z. H.; Al Anazi, F. E.; Alsaad, A. M.; Alanazi, I. O.; Belali, O. M.; Al-Atawi, F. O.; Alshamsan, A. (2017-09-06). "Sunitinib Inhibits Breast Cancer Cell Proliferation by Inducing Apoptosis, Cell-cycle Arrest and DNA Repair While Inhibiting NF-ĸB Signaling Pathways". Anticancer Research. 37 (9): 4899–4909. doi: 10.21873/anticanres.11899 . ISSN   0250-7005. PMID   28870911.
  16. ↑ Hardman, J. G.; Limburd, L. E.; Gilman, A. G., eds. (2000). Goodman & Gilman's The Pharmacological Basis of Therapeutics (10th ed.). New York: McGraw-Hill. ISBN   978-0-07-135469-1.
  17. ↑ Chien, S; Toledo-Pereyra, L, eds. (2008). 'Metabolic Management - Organ Procurement and Preservation For Transplantation. New York: Landes Bioscience Springer. Retrieved 11 April 2016.
  18. ↑ Haynes RH (1988). Biological context of DNA repair. In: Friedberg EC & Hanawalt PC editors, Mechanisms and Consequences of DNA Damage Processing, John Wiley & Sons Canada, Limited, 1988 pp. 577-584. ISBN   0471502693, 9780471502692
  19. 1 2 Bernstein, C; Bernstein, H; Payne, CM; Garewal, H (2002). "DNA repair/pro-apoptotic dual-role proteins in five major DNA repair pathways: fail-safe protection against carcinogenesis". Mutat Res. 511 (2): 145–178. doi:10.1016/s1383-5742(02)00009-1. PMID   12052432.
  20. ↑ Narayanan, L; Fritzell, JA; Baker, SM; Liskay, RM; Glazer, PM (1997). "Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2". Proc Natl Acad Sci U S A. 94 (7): 3122–3127. Bibcode:1997PNAS...94.3122N. doi: 10.1073/pnas.94.7.3122 . PMC   20332 . PMID   9096356.
  21. ↑ Hegan, DC; Narayanan, L; Jirik, FR; Edelmann, W; Liskay, RM; Glazer, PM (2006). "Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6". Carcinogenesis. 27 (12): 2402–2408. doi:10.1093/carcin/bgl079. PMC   2612936 . PMID   16728433.
  22. ↑ Tutt, AN; van Oostrom, CT; Ross, GM; van Steeg, H; Ashworth, A (2002). "Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation". EMBO Rep. 3 (3): 255–260. doi:10.1093/embo-reports/kvf037. PMC   1084010 . PMID   11850397.
  23. ↑ Sedelnikova, OA; Redon, CE; Dickey, JS; Nakamura, AJ; Georgakilas, AG; Bonner, WM (2010). "Role of oxidatively induced DNA lesions in human pathogenesis". Mutat Res. 704 (1–3): 152–159. doi:10.1016/j.mrrev.2009.12.005. PMC   3074954 . PMID   20060490.
  24. ↑ Ames, BN; Shigenaga, MK; Hagen, TM (September 1993). "Oxidants, antioxidants, and the degenerative diseases of aging". Proc. Natl. Acad. Sci. U.S.A. 90 (17): 7915–22. Bibcode:1993PNAS...90.7915A. doi: 10.1073/pnas.90.17.7915 . PMC   47258 . PMID   8367443.
  25. ↑ Sakai, A; Nakanishi, M; Yoshiyama, K; Maki, H (2006). "Impact of reactive oxygen species on spontaneous mutagenesis in Escherichia coli". Genes Cells. 11 (7): 767–778. doi: 10.1111/j.1365-2443.2006.00982.x . PMID   16824196. S2CID   1365658.
  26. ↑ Massie, HR; Samis, HV; Baird, MB (1972). "The kinetics of degradation of DNA and RNA by H2O2". Biochim Biophys Acta. 272 (4): 539–548. doi:10.1016/0005-2787(72)90509-6. PMID   5065779.
  27. ↑ Vilenchik, MM; Knudson, AG (2003). "Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer". Proc Natl Acad Sci U S A. 100 (22): 12871–12876. Bibcode:2003PNAS..10012871V. doi: 10.1073/pnas.2135498100 . PMC   240711 . PMID   14566050.
  28. 1 2 Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In: New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47. open access, but read only https://www.novapublishers.com/catalog/product_info.php?products_id=43247 Archived 2014-10-25 at the Wayback Machine ISBN   1604565810 ISBN   978-1604565812
  29. 1 2 Chatterjee, N; Walker, G (June 2017). "Mechanisms of DNA damage, repair and mutagenesis". Environmental and Molecular Mutagenesis. 58 (5): 235–263. doi:10.1002/em.22087. hdl: 1721.1/116957 . PMC   5474181 . PMID   28485537.
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