Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment


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Introduction

Simic Synopsis: This book is based on the papers presented at the conference on Mecha nisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment, held at the National Bureau of Standards on June , , This volume deals with mechanisms of DNA damage and repair at the molecular level; consequences of unrepaired or misrepaired damage, with major emphasis on carcinogenesis; drugs which bind selectively to altered and potentially damaging DNA sequences; and potential utilization of DNA damage as an endpoint for assessing risks of UV light, ionizing radiations, chemicals, drugs, and hazardous agents in foods.

Because the induction of mutations by radiation and genotoxic chemicals has been observed to follow one-hit kinetics in some instances, it is generally assumed that any level of exposure to a DNA-damaging agent may increase the risk of genetic disease or cancer in an exposed population. At the same time, however, there is evidence that although the DNA of living cells is continually damaged by natural background radiation, free radicals, and other naturally occurring processes, most of the damage is normally repaired. Matowitz Jr. Mostafa Ghiaasiaan.

David N. Ashton Acton, PhD. Free Book Duma key by Stephen King.

Mechanisms of DNA Damage and Repair

Free Book Entends la nuit by Catherine Dufour. Free Book Infestation by Ezekiel Boone. Nolan Clark. Free Book L'organisation des talents by Suzanne Williams. The process of malignant transformation involves a series of changes that follow, at least roughly, a functional and temporal sequence by which cells gradually and progressively escape from normal tissue control and acquire independence, diversity, and invasive properties figure 6. Molecular changes associated with radiation carcinogenesis have mainly been investigated after higher doses and dose rates than those experienced from background levels of radon exposure.

Therefore these changes are described qualitatively and the extent to which any or all occur in tissues in which a small proportion of cells have experienced a single alpha particle track remains to be determined. Inhalation of radon results in exposure of lung cells to alpha irradiation from radon progeny, which are deposited in the mucus layer and can result in exposure.

Ingestion of waterborne radon might, on first impression, similarly expose the cells of the stomach lining. After ingestion, however, radon travels as gas molecules with high mobility through cell membranes, and cells may receive a more uniform exposure. Stem cells and other proliferating cells of the stomach are found in bands at the bases of the necks of narrow invaginations of the stomach wall that constitute the secretory glands of the stomach wall Nomura Stem cells and other proliferative cells of the stomach are major targets of radon alpha particles, but cells of the small intestine are also potential targets.

After ingestion of water, radon passes into the small intestine with a half-time of about 15—20 minutes.

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Radon can therefore be absorbed into the bloodstream from both the stomach wall and the small intestine. The resulting exposures to most cells of the body will then be through bloodborne radon. From that point of view, the stomach might be at greatest risk of exposure from ingested, aqueous radon.

The transfer of dissolved radon from water to air and its later inhalation constitute another route by which the lungs can be at risk. Implicit in these scenarios is the idea that the cells most likely to become malignant are the stem cells and proliferative cells that retain the capacity for continued division and can fix and express permanent genetic change.

DNA Damage, DNA Repair and Cancer

Malignant cells often retain characteristic enzymatic and cellular features of their tissue of origin, so the differentiation and specialization programs of cells might be altered but not completely abrogated by the malignant-transformation process. Alpha-particle damage to genetic material becomes fixed as permanent alterations to gene structure and expression as a result of processes that involve DNA repair, replication, and cell division.

The stem cells of epithelial tissues are embedded in crypts; this renders them relatively inaccessible to direct contact with ingested or inhaled radon. Stem cells will, however, still be exposed to alpha irradiation from the lumen or blood stream, from intercellular and intracellular water, and after inhalation from decay products that plate out and act as additional sources of radiation damage.

An additional factor to be considered is the potential role of chronic stomach infections. A large fraction of the normal human population carry Helicobacterpylori infections in the stomach that can cause gastritis and, in severe cases, ulcers.


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The inflammation and proliferation associated with these infections can be a factor in the induction and progression of stomach cancer and have been regarded as risk factors McFarlane and Munro Alpha particles create dense ionization that leaves tracks of ion-pair clusters across cells and tissues. Cells that suffer an alpha-particle track through the nucleus are severely injured. For comparison, it requires an exposure of WLM to reach the level at which the average exposure to stem cells reaches one alpha particle per nucleus Harley and others Therefore, complex considerations of dose rates and total doses that are important for miners or other people with high occupational exposure are unimportant in consideration of domestic exposure Brenner and others ; Brenner see also BEIR VI report National Research Council Alpha particles traverse a cell in less than 10 seconds and deposit energy corresponding to about 10—50 cGy Jostes As the particles slow down, they deposit increasing amounts of energy linear energy transfer, or LET per unit length of track, reaching a maximum at the end of their track at what is known as the Bragg peak.

The relative biologic effectiveness RBE of an alpha particle is therefore variable along its track according to whether the LET reaches a maximum at the Bragg peak Brenner and others The average track through a spherical cell nucleus can cross many individual strands of DNA, depositing energy in the form of clusters of ionizations, and produce corresponding numbers of double-strand breaks. These breaks have a complex chemistry and have been described as multiply locally damaged sites MLDSs Ward Because of the track structure and the tightly coiled nature of DNA in the nucleus, there is likely to be a nonuniform distribution of DNA breaks with an excess of small fragments which might get lost or incorrectly positioned in the process of rejoining Ritter and others Ion clusters can also produce reactive oxygen intermediates which can damage individual DNA bases, and at high doses, alter intracellular signal transduction, reduce macromolecular synthesis, and trigger processes that resemble those from inflammatory cytokines involved in other kinds of tissue injury.

A series of early experiments in the and s used collimated beams of alpha particles and other kinds of radiation and demonstrated the relative importance of nuclear, cytoplasmic, and extracellular irradiation Munro b; a; Smith Those experiments showed that nuclear damage was potentially lethal; nonnuclear damage could also produce detectable effects, such as reduced DNA synthesis, but it was not lethal.

Extracellular damage involved reactive oxygen intermediates that could be prevented by catalase which degrades hydrogen peroxide Dendy and others More recent and technically sophisticated experiments in which the effects of single alpha particles can be estimated or observed have resulted in essentially similar conclusions Hei and others ; Hickman and others The dose required to produce an average of one lethal hit to a cell the D 37 corresponds to about 1. Flattened cells can withstand more tracks up to 15 or even more , each of. Lethality can be related to the net absorption of a particular amount of total energy per cell, measured along a total path length through the nucleus—either a single track through a spherical nucleus or several shorter tracks through a flat nucleus.

Calculations indicate a constant probability of 0. All radon alpha-particle effects at the low doses associated with environmental exposure from water occur from the passage of single particles through a small proportion of the cells in a tissue, so the dose-effect relationship will be a linear function of dose, with no dose-rate effects.

This is true because variations in exposure change the number of cells hit by an alpha particle, rather than the amount of damage per cell. To calculate cancer risk it is then necessary to know the probability that a hit cell will undergo transformation, and the latent period and its age distribution before transformation to malignancy is complete. The latent period for single cells exposed to single tracks of alpha particles is unknown, but if it were long compared to the lifespan of the individual, the cancer risk would be correspondingly reduced, as suggested by Raabe The important cellular subpopulation for carcinogenesis is not that of the rare cells killed by alpha-particle damage, but that of the cells that survive either with direct damage to their genetic material or with altered genomic stability.

Because the calculated D 37 is more than one alpha particle per cell in very low exposures, such as to ambient air or water, most exposed cells should survive, because it is extremely rare for any cell to be hit more than once. That might also account for the strong synergism displayed between radon exposure and cigarette-smoking: initial radon exposure leaves a viable, damaged cell, which is then stimulated further by the carcinogens found in cigarette smoke Moolgavkar and others ; Brenner and Ward Low-dose exposure also raises the question of whether radon alpha particles can give rise to radiation hormesis—the phenomenon whereby very low radiation doses are stimulatory and beneficial Ueno and others If hormesis occurs through a stimulation of some kind of repair, the low stimulating dose must induce an excess repair capacity that can mend not only the damage caused by the initial dose, but also pre-existing endogenous cellular damage.

That has been observed for repair of mitochondrial oxidative damage Driggers and others but, evidence generally is indirect and difficult to obtain. Evidence of radiation hormesis is consequently controversial and will not be further considered here. Although extranuclear damage and extracellular ionization might play a role in some biologic effects known as bystander effects , they are unlikely to play an important role in cell-killing Hickman and others ; Dendy and others The flow of events that follow the production of DNA damage and other forms of cellular damage is therefore critical in understanding the development of malignancies.

Low doses of alpha particles which simulate radon exposure have been used to achieve malignant transformation of cultured cells in studies aimed at measuring their biological effectiveness and estimating carcinogenic hazards. In general, normal diploid cells, with the exception of some hamster embryo cells, have extremely low transformation rates after irradiation. Studies of transformation therefore often use cells such as mouse 3T3 in which genetic changes have already occurred that increase their overall genetic instability and hence their transformability.

Although many of these studies generated linear dose-response curves over the dose ranges used Miller and others ; ; Brenner and others ; Ling and others , some indicated a nonlinear response with greater effectiveness at the lowest doses Martin and others ; Bettega and others Considerable uncertainty, therefore, still exists about the precise shape of the dose-response relationship for transformation of cells in culture, and by implication, also for carcinogenesis. The results in general do not permit a definitive answer to be obtained for the shape of the dose-response curve at the lowest doses and dose rates, but at the same time there is no compelling evidence to adopt any one particular nonlinear dose-effect relationship.

The many and varied biological changes over long time periods that are involved in carcinogenesis, which are discussed in the following sections, indicate that many factors can be expected to influence the shape of the dose-response relationship. The gene products responsible for sensing damaged DNA and carrying out repair, euphemistically called the cellular caretakers Kinzler and Vogelstein , involve a number of enzymatic systems capable of mending single-and double-strand breaks in DNA and excising damaged and mismatched bases.

Implications for Carcinogenesis and Risk Assessment

Double-strand breaks are the most important kinds of damage resulting from radon alpha particles. They can be repaired through at least two pathways: homologous recombination figure 6. Repair through homologous or nonhomologous recombination involves complex sets of enzymes, which share components with enzymes and gene products associated with the generation of immunoglobulin diversity, such as RAG1 and RAG2 Melek and others and with mitotic and meiotic recombination Jeggo and others ; Jeggo Most mammalian somatic cells are in the prereplicative, G 1 , phase of the cell cycle and double-strand break repair appears to involve the nonhomologous, or illegitimate, end-joining reactions Jeggo and others In large part, that is because the homologous chromosomes in a diploid G 1 nucleus are widely separated, so nonhomologous recombination can occur at about 10 4 times the efficiency of homologous recombination Godwin and others ; Benjamin and.

Mechanism of double strand break repair by homologous recombination through hybridization of the broken DNA strands sequences on the undamaged homolog. A DNA terminus is paired with the intact DNA by the action of pairing proteins including Rad51 and many other associated proteins that modulate its functions and carry out the numerous steps of pairing, elongation of DNA termini, and migration of hybridizing junction regions.

The extent of sequence overlap can be very long, up to kilobases in length, and requires exact matching of DNA along most of the length of the hybrid molecules. Raddependent DNA pairing is suppressed by prad51 interaction, which is also a route for initiating intracellular pdependent signal transduction pathways. Broken double stranded DNA indicated by a,b; recipient intact strands by c,d; strands created by strand extension c', d'.

De novo synthesis indicated by ——. Repair of a double strand break will require two of these homologous exchange events, one for each terminus. Some resolved DNA products may be visualized at the chromosomal level in mitotic cells as a sister chromatid exchange. Little The relative importance of those pathways can vary with cell-cycle stage, tissue type, developmental stage and species. Direct measurement of DNA breakage and repair indicates that double-strand breaks can be rejoined rapidly—within a few hours.

There is, however, a residuum of unrepaired damage that is greater for densely ionizing radiation, such as alpha particles, than for x rays Ager and others ; Iliakis ; Iliakis and others ; Ward Although it is unknown if high levels of alpha-particle damage saturate DNA-repair systems, such potential saturation would not be relevant at low-dose ambient. Mechanism of nonhomologous illegitimate recombination at sites of double strand breakage in DNA.

Thresholds of Genotoxic and Non-Genotoxic Carcinogens

The ends are sites of association of end-binding proteins, Ku70, Ku86, and p DNA-dependent kinase. After limited exonucleolytic degradation, short single stranded DNA termini that may not necessarily be from either side of the original break with a few nucleotides that can form base-pairs will hybridize and local regions can then be patched by DNA polymerase b and ligase. The extent of sequence overlap is very short, usually less than 10 nucleotides more often 1 to about 5.

The p kinase interacts with p53 and initiates intracellular signal transduction pathways. More important, even at low doses, is whether any kinds of damage are completely irreparable and whether repair is always accurate.


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Persistent genetic changes caused by radiation must then be caused by repair that misassembles broken termini from distant regions of the genome and triggers a lasting genetic instability. Homologous rejoining involves matching of a broken fragment with the corresponding region on the undamaged homologous chromosome followed by strand invasion and reconstruction of the damaged region by replication of the sequence information in the intact homologue figure 6.

It requires that the two homologues are within range of each other; consequently, it might be more important for replicating cells in late S and G 2 phases of the cell cycle when sister chromatids are in close apposition Takata and others in press; Sonoda and others ; Thompson and contributes to increased radio-resistance in these phases of the cell cycle Cheong and others This form of double-strand repair is likely to be highly accurate because of the use of sequence information from the intact chromosomal homologue chromatid in reconstructing the broken DNA.

The Rad51 protein. Rad51 is inhibited by association with the tumor suppressor p53 Buchhop and others and interacts with the breast-cancer-specific gene products Brcal and Brca2 Scully and others b; Scully a. Knockout of the Rad51 and the Brcal and Brca2 genes result in early embryo death Lim and Hasty ; Tsuzuki and others ; this suggests a complex regulatory scheme for homologous recombination during development and carcinogenesis. The nonhomologous recombination pathway for repair of radiation-induced DNA breakage in somatic cells involves an end-to-end rejoining reaction in which broken ends of DNA are braced by a set of supporting proteins.

The gap between DNA ends is bridged by overlapping single-strand termini that are usually less than 10 nucleotides long more commonly one to five long and a set of proteins, including Ku70, and Ku86, p kinase, and DNA ligase IV Kirchgessner and others ; Lees-Miller and others ; Getts and Stamato ; Rathmell and Chu ; Smider and others ; Taccioli and others ; Anderson figure 6. The p kinase interacts with p53, the major signaling protein that regulates cell-cycle control, apoptosis, and the transcription of many downstream genes Elledge and Lee ; Kastan and others ; Lane Defects in p have been associated with the systemic combined immunodeficiency scid phenotype in mice Kirchgessner and others Knockout of the Ku70 and Ku86 genes renders cells more sensitive to ionizing radiation but, unlike the genes involved in homologous recombination, does not result in embryo death.

The rejoining reaction results in a junction made by an overlap of a few bases at each terminus with additional possibilities of single-base or larger insertions, deletions, or mismatches. No consistent DNA-sequence motifs have been found in these short regions of sequence overlaps, despite direct investigation of micro-satellite repeats and telomere and triplet repeat sequences.

Insertions can be many kilobases long and can come from locally produced fragments or from single-strand invasion into proximal regions of DNA. The ends involved in rejoining reactions are not necessarily those from either side of the initial break but can be from other breaks made by the same alpha track. The intervening stretch of DNA can then be lost, with consequent chromosomal rearrangement. These losses and rearrangements can involve many kilobases of DNA, producing the losses, deletions, and rearrangements of genetic material which are hallmarks of genetic effects caused by densely ionizing radiation Zhu and others ; Kronenberg and others ; Nelson and others ; Phillips and Morgan The process of DNA breakage and rejoining therefore initiates a major change in signal transduction and cellular regulation that can persist over many cell generations see discussion of genetic instability below.

The ion pairs that do not directly damage DNA can produce reactive oxygen intermediates.

Reactive oxygen intermediates can produce oxidative damage, of which 8-oxy-guanine is a major product. Oxidations are produced in DNA and in both deoxyribose and ribose triphosphates. MutT activity reduces mutations from naturally occurring oxidative reactions by a factor of about 10 4.

Oxidative damage involves production of damaged individual bases, such as 8-oxy-G, and many other products in DNA that cause point mutations by mispairing during DNA replication Singer and that are repaired by the base-excision repair system. Base excision involves a set of glycosylases with limited ranges of substrate specificity uracil, 3-methyladenine, formamidopyrimidine, glycosylases and others.

DNA breaks and other base damage therefore are the assembly points for complex, multifunctional, multipurpose structures that signal their presence to many other cellular processes and within which repair and genetic changes occur. The combined actions of these cellular caretakers produces surviving cells that bear the permanent marks of alpha particle exposure, including deletions, insertions, amplifications, point mutations, and altered cellular regulation Kronenberg and others ; Kronenberg The end result of DNA breakage and rejoining is the deletion, insertion or rearrangement of various amounts of genetic material, from a few base pairs.

Chromosomal fragments that are not rejoined can be excluded from interphase nuclei and can form micronuclei. These micronuclei, which encapsulate p53 Unger and others can be scored as a quantitative measure of chromosomal damage in somatic and cultured cells. The size of deletions that persist in surviving cells is determined by the initial spacing of DNA double-strand breaks and by the presence of vital genes in the intervening sequences. Deletion sizes associated with loss of function of the adenine phosphoribosyl transferase APRT gene, for example, are generally smaller than those associated with loss of function of the hypoxanthine phosphoribosyl transferase HPRT gene because of the presence of vital genes closer to APRT than HPRT Park and others ; Nelson and others ; Fuscoe and others ; Morgan and others ; Thompson and Fong Deletion sizes and junction positions are markedly nonrandom in both the chromosomal HPRT gene and in episomal vectors that carry reporter genes.

The positions of DNA breaks and the efficiency and precision of their repair are therefore strongly influenced by chromatin structure and attachment of DNA to nucleosomal and matrix proteins and the functions of flanking genes. In an experimental cell-culture system in which a single human chromosome bearing a marker gene is carried in a hamster cell line the A L cell line , very few of the human genes are required for cell survival, and alpha-particle damage can produce very large deletions that involve most of the chromosome Hei and others ; Ueno and others This situation cannot apply to most chromosomes in a normal cell, in which deletion sizes consistent with survival will be limited by the presence of important genes distributed throughout the genome.

One gene product, the p53 protein figure 6. The p53 protein is a rapidly synthesized, but short-lived, multifunctional protein which interacts with a wide array of other cellular and viral proteins and binds to DNA in both sequence-specific and sequence-independent fashions. In the presence of damage either DNA breaks or reactive oxygen intermediates the lifetime of p53 increases, it is phosphorylated at specific sites that depend on the particular signal, and it acts as a transcriptional activator with downstream effects on many other genes, especially stimulating transcription of p21, which then inhibits cell-cycle progression.

Alpha-particle irradiation at low exposures has been shown to result in p53 stabilization in more cells than could have experienced alpha-particle tracks: this suggests that reactive oxygen intermedi-. The level of damage and of consequent p53 function plays a major role either in causing cell-cycle delays through activation of the p21 gene, which blocks cells in the G 1 phase or in initiating apoptosis.

Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment
Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment
Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment
Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment
Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment Mechanisms of DNA Damage and Repair: Implications for Carcinogenesis and Risk Assessment

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