Different inherited levels of DNA repair replication in xeroderma pigmentosum cell strains after exposure to ultraviolet irradiation.
TL;DR: Primary fibroblast cultures were established from 8 patients having different degrees of clinical symptoms of xeroderma pigmentosum, suggesting a genetically determined constant level of reduced repair replication.
Abstract: Primary fibroblast cultures were established from 8 patients having different degrees of clinical symptoms of xeroderma pigmentosum. Repair replication after exposure of cells to different doses of ultraviolet irradiation (predominantly 254 nm) was studied by means of [ 3 H] thymidine labeling and autoradiography. A decreased repair DNA synthesis in cells in G 1 and G 2 phase was found in all xeroderma pigmentosum cell cultures relative to control cell cultures obtained from healthy people. Cell strains originating from two severe cases of xeroderma showed no repair synthesis after short autoradiographic exposure times, although, after one-month exposure a slight labeling was observed (10–20% of the control). The repair activity in cells from the other patients ranged from 70% for a light case to 50 and 30% for moderate cases of the disease. Cells obtained from related patients showed identical levels of repair activity, suggesting a genetically determined constant level of reduced repair replication. A xeroderma cell strain transformed by SV 40 virus showed no repair replication as did the original strain before transformation.
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719 citations
TL;DR: Clinical features of xeroderma pigmentosum; karyotype; cell killing and host cell reactivation after irradiation or exposure to chemical carcinogens ; biochemical defects in the common and de Sanctis-Cacchione forms of xERoderma pigments; cell hybridization and complementation groups.
Abstract: Biochemical and genetic studies on xeroderma pigmentosum are reviewed under the following headings: clinical features of xeroderma pigmentosum; karyotype; cell killing and host cell reactivation after irradiation or exposure to chemical carcinogens; SV40 transformation of xeroderma pigmentosum cells; biochemical defects in the common and de Sanctis-Cacchione forms of xeroderma pigmentosum; cell hybridization and complementation groups; biochemical defects in the xeroderma pigmentosum variant and the role of caffeine in DNA repair; DNA repair in xeroderma pigmentosum heterozygotes; response of xeroderma pigmentosum cells to various mutagens and chemical carcinogens; other high and low repair diseases; and possible significance of DNA repair in theories of aging and carcinogenesis. (HLW)
380 citations
TL;DR: Using the dark repair mechanism in microorganisms as a model, evidence has been presented that XP cells are defective in the incision step of DNA repair3–5.
Abstract: XERODERMA pigmentosum is an autosomal recessive disease characterized by hypersensitivity of the skin to ultraviolet radiation resulting in severe skin lesions. DNA repair replication after ultraviolet irradiation is absent or markedly reduced in cultivated fibroblasts from patients with xeroderma pigmentosum (XP cells) compared with normal cells1,2. Using the dark repair mechanism in microorganisms as a model, evidence has been presented that XP cells are defective in the incision step of DNA repair3–5.
300 citations
Book•
10 Mar 1981
TL;DR: The author reveals a possible molecular Mechanism for Rejoining Between a Telomere and a Break and the Stabilization of a Broken End that has not yet been found in the literature.
Abstract: 1. Quantitative Radiation Biology.- 1.1 Radiation in Society.- 1.2 Radiation Biology: the Interdisciplinary Discipline.- 1.3 The Importance of Cellular Biology.- 1.4 The Quantitative Analysis of Radiation Action: a Brief Historical Review.- 1.5 Desiderata for a Quantitative Theory of Radiation Biology.- 2. The DNA Molecule and Its Role in the Cell.- 2.1 Introduction.- 2.2 The Structure and Dimensions of the DNA Molecule.- 2.3 Base Sequences and the Genetic Code.- 2.4 DNA Replication.- 2.5 DNA in Chromosomes.- 2.6 The Diploid Cell, Mitosis and Meiosis.- 2.7 Radiation-Induced Damage to DNA.- 2.7.1 DNA Base Damage.- 2.7.2 DNA Single Strand Breaks.- 2.7.3 DNA Double Strand Breaks.- 3. The Molecular Model for Cell Survival Following Radiation.- 3.1 Historical Development.- 3.2 The Philosophical Framework of the Model.- 3.3 The Induction of DNA Double Strand Breaks by Radiation.- 3.3.1 The Induction of DNA Single Strand Breaks.- 3.3.2 The Induction of DNA Double Strand Breaks in One Radiation Event.- 3.3.3 The Induction of DNA Double Strand Breaks in Two Radiation Events.- 3.3.4 The Total Induction of DNA Double Strand Breaks.- 3.3.5 The Induction of DNA Double Strand Breaks with Repair.- 3.3.6 The Influence of Base Damage on the Production of Double Strand Breaks.- 3.4 The Relationship Between Cell Survival and DNA Double Strand Breaks.- 3.5 The Cell Survival Curve.- 3.5.1 Cell Survival as Criterium.- 3.5.2 Correction for Cell Multiplicity.- 3.5.3 The Shape of the Cell Survival Curve.- 3.5.4 The Analysis of Experimental Data.- 3.6 Variation in the Survival Curve Through the Cell Cycle.- 3.7 Asynchronous Cell Populations.- 3.8 The Experimental Correlation Between Cell Survival and DNA Double Strand Breaks.- 3.9 Summary.- 4. Chromosomal Aberrations.- 4.1 Introduction.- 4.2 The Nature and Yield of Chromosomal Aberrations.- 4.3 The Classical and Exchange Theories of Radiation- Induced Chromosomal Aberrations.- 4.3.1 The Classical Theory.- 4.3.2 The Exchange Theory.- 4.3.3 The Problem.- 4.4 The Molecular Theory of Radiation-Induced Chromosomal Aberrations.- 4.4.1 The Yield of Chromosomal Aberrations.- 4.4.2 The Formation of Chromosomal Aberrations by the Process of Telomere-Break Rejoining.- 4.4.2.1 A Possible Molecular Mechanism for Rejoining Between a Telomere and a Break and the Stabilization of a Broken End.- 4.4.3 The Formation of Chromosomal Aberrations by the Process of Recombinational Rejoining.- 4.4.3.1 Repetitive DNA.- 4.4.3.2 Palindromes.- 4.4.3.3 Incompleteness.- 4.4.4 The Experimental Evidence for Telomere-Break Rejoining.- 4.4.4.1 The Haplopappus Experiment.- 4.4.4.2 Other Radiation Experiments.- 4.4.4.3 Medical Cytology.- 4.4.5 The Experimental Evidence for the Process of Recip--rocal Recombination.- 4.4.6 Two Mechanisms for the Formation of Chromosomal Aberrations?.- 4.4.6.1 The Molecular Nature of the Telomere.- 4.4.6.2 The Role of Caffeine.- 4.5 Complex Chromosomal Rearrangements.- 4.6 Gene Transplantation.- 4.7 Summary.- 5. Somatic Mutations.- 5.1 Point and Chromosome Mutations.- 5.2 Some Molecular Mechanisms Which Could Give Rise to Mutations from DNA Double Strand Breaks.- 5.2.1 The Rejoining of Single Stranded Tails.- 5.2.2 Resnick's Model for Gene Conversion.- 5.2.3 Resnick's Model for Reciprocal Recombination.- 5.2.4 Rejoining Between a Telomere and a Single Stranded Tail.- 5.2.5 No Repair.- 5.2.6 The Repair Processes and Mutation Induction.- 5.3 Mutation Frequency Dose Relationships.- 5.3.1 The Induction of Mutations.- 5.3.2 The Suppression of Mutation Expression.- 5.3.3 The Influence of Cell Killing.- 5.4 The Analysis of Experimental Data.- 5.5 Two Mutations in the Same Cell Population.- 5.6 The Mutation Spectrum.- 5.7 Summary.- 6. Correlations.- 6.1 Introduction.- 6.2 The Survival-Survival Correlation.- 6.3 The Survival-Chromosomal Aberration Correlation.- 6.4 The Correlation Between Different Chromosomal Aberrations.- 6.5 The Correlation Between "Normal" Chromosomal Aberrations and "Complex" Chromosomal Aberrations.- 6.6 The Correlation Between Survival and Somatic Mutation.- 6.7 The Correlation Between Two Different Mutations Induced in the Same Cell Population.- 6.8 The Peak Incidence - an Implied Correlation.- 6.9 What Do the Correlations Mean?.- 7. Repair.- 7.1 Introduction.- 7.2 The Repair of DNA Single Strand Breaks and the Dose Rate Effect.- 7.2.1 Experimental Evidence on DNA Single Strand Break Repair.- 7.2.2 The Time Scale of the Three Dose Rate Regions.- 7.2.3 The Exponential Repair of DNA Single Strand Breaks and Its Effect on the Dose Response Relationships.- 7.2.4 Implications for the InS/D Versus D Analysis.- 7.2.5 Complicated Repair Rates.- 7.2.6 Practical Difficulties in the Determination of Dose-rate Effects.- 7.3 The Repair of DNA Single Strand Breaks and the Effect of Dose Fractionation.- 7.3.1 The Analysis of Repair Using Fractionation Studies.- 7.4 The Repair of DNA Double Strand Breaks and the Post-Irradiation Effect.- 7.4.1 The Quantitative Effect of DNA Double Strand Break Repair on Cell Survival.- 7.4.1.1 The Time Dependence of the Repair of DNA Double Strand Breaks.- 7.4.2 The Quantitative Effect of DNA Double Strand Break Repair on Chromosomal Aberration Yield.- 7.4.3 The Quantitative Effect of DNA Double Strand Break Repair on Mutation Frequency.- 7.4.4 Is the Efficiency for the Repair of DNA Double Strand Breaks Always Dose-independent?.- 7.5 The Difference Between Sub-lethal Damage Repair and Potentially Lethal Damage Repair.- 8. Radiation Quality.- 8.1 The Differing Shape of Dose-response Relationships.- 8.2 A Qualitative Assessment of the Dependence of the ?-Coefficient on Radiation Quality.- 8.3 A Qualitative Assessment of the Dependence of the ?-Coefficient on Radiation Quality.- 8.4 How Constant is the Value of RBEo?.- 8.4.1 The Variation of RBEo in the Cell Cycle.- 8.4.2 The Effect of Different Conditions in the Cell.- 8.4.3 Extremely High Values of RBEo.- 8.5 The Size of the Target.- 8.6 A Calculation of the Dependence of the a- and ss- Coefficients on Radiation Quality.- 8.6.1 The Track Model.- 8.6.2 A Calculation of the Induction of DNA Single and Double Strand Breaks.- 8.6.3 A Quantitative Assessment of the Dependence of Cell Survival on Radiation Quality.- 8.6.4 The Relation Between Physics, Chemistry, and Biology.- 8.7 Summary.- 9. Cancer.- 9.1 Introduction.- 9.2 Somatic Mutation and Cancer.- 9.2.1 Historical Development.- 9.2.2 The Modern Evidence Supporting the Somatic Mutation Theory.- 9.2.2.1 The Mutagen Screening Tests.- 9.2.2.2 The Typical Chromosomal Aberrations.- 9.2.2.3 The Repair-deficient Human Disorders.- 9.3 The Malignant Cell.- 9.4 Radiation-Induced Cell Transformation.- 9.4.1 The Diploid Carrier Cell.- 9.4.2 The Tetraploid Carrier Cell.- 9.4.3 The Diploid Non-Carrier Cell.- 9.5 Extrapolation to Animals and Man.- 9.5.1 Experimental Data for Animals.- 9.5.2 Radiation-induced Malignancy in Man.- 9.5.2.1 Sparsely Ionizing Radiation.- 9.5.2.2 Densely Ionizing Radiation.- 9.6 Conclusion.- 10. Genetic Effects.- 10.1 Introduction.- 10.2 The Induction of Dominant Lethal Mutations.- 10.3 Correlations Between Different Genetic End Points.- 10.3.1 The Correlation Between Dominant Lethality and the Yield of Chromosomal Aberrations.- 10.3.2 The Correlation Between Different Chromosomal Aberrations.- 10.3.3 The Correlation Between Dominant Visible Mutations and Specific Locus Mutations in the Mouse.- 10.3.4 The Correlation Between Dominant and Recessive Lethal Mutations.- 10.4 The Induction of Translocations in the Spermatogonia of the Mouse.- 10.4.1 The Spermatogonial Stem Cell Development.- 10.4.2 Acute Irradiation.- 10.4.3 The Effect of Dose Rate.- 10.4.4 Short-Term Fractionation.- 10.4.5 Twenty-Four-Hour Fractionation.- 10.4.6 Long-Term Fractionation.- 10.5 The Induction of Specific Locus Mutations in the Mouse.- 10.6 Conclusions.- 11. Synergistic Interaction.- 11.1 Introduction.- 11.2 Theoretical Development.- 11.3 Agent Toxicity.- 11.4 Agent Dosimetry.- 11.5 Experimental Examples of Synergism.- 11.5.1 The Interaction of Radiation with UV.- 11.5.2 The Interaction of Radiation with Halogenated Pyrimidine Analogues.- 11.5.3 The Interaction of Radiation with Nitrosourea Compounds.- 11.5.4 The Interaction of Radiation with Diamide.- 11.6 General Discussion.- 12. Implications.- 12.1 Radiological Protection.- 12.1.1 Sparsely Ionizing Radiation.- 12.1.2 Densely Ionizing Radiation.- 12.1.3 Cancer as a Recessive Genetic Character.- 12.1.4 Genetic Effects.- 12.1.5 The Effect of Environmental Mutagens.- 12.2 The Chemical Hazard.- 12.3 Radiation Therapy.- 12.3.1 Fractionation.- 12.3.1.1 ?-Type Sensitizer.- 12.3.1.2 ?-Type Sensitizer.- 12.3.1.3 Implications for the Choice of Sensitizer.- 12.4 Plant Mutation Breeding.- 12.5 Postscript.- References.- List of Abbreviations.
244 citations
TL;DR: The subjects are three patients with distinct symptoms of xeroderma pigmentosum in which the cultured fibroblasts are different from those usually found in this disease, and a minority of those cases which are clinically diagnosed as XP constitute a biochemically distinct condition.
239 citations
References
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TL;DR: Patients with xeroderma pigmentosum develop fatal skin cancers when exposed to sunlight, and so the failure of DNA repair in the skin must be related to carcinogenesis.
Abstract: Normal skin fibroblasts can repair ultraviolet radiation damage to DNA by inserting new bases into DNA in the form of small patches. Cells from patients with the hereditary disease xeroderma pigmentosum carry a mutation such that repair replication of DNA is either absent or much reduced in comparison to normal fibroblasts. Patients with xeroderma pigmentosum develop fatal skin cancers when exposed to sunlight, and so the failure of DNA repair in the skin must be related to carcinogenesis.
1,649 citations
TL;DR: Homozygous xeroderma pigmentosum fibroblasts cannot repair damage to DNA bases, but can repair damage that involves chain breaks, and may be the result of somatic mutations caused by unrepaired damage.
Abstract: Homozygous xeroderma pigmentosum fibroblasts cannot repair damage to DNA bases, but can repair damage that involves chain breaks. In xeroderma pigmentosum, therefore, there is a defect in an early step in repair at which base damage is recognized and the polynucleotide chain broken enzymatically (by an endonuclease). Heterozygous fibroblasts repair base damage to normal extents. Carcinogenesis in xeroderma pigmentosum, and perhaps in some normal individuals, may be the result of somatic mutations caused by unrepaired damage.
392 citations
TL;DR: The number of breaks in the polynucleotide chains of the DNA in murine leukaemia cells, the bacterium Micrococcus radiodurans and in Isolated DNA are approximately the same and the results suggest that the molecular weight of the mammalian DNA is very high.
Abstract: The number of breaks produced by X-rays In the polynucleotide chains of the DNA in murine leukaemia cells, the bacterium Micrococcus radiodurans and in Isolated DNA are approximately the same. The leukaemia cells have an efficient system for rejoining broken strands. The results also suggest that the molecular weight of the mammalian DNA is very high.
291 citations
TL;DR: Within 12-24 hr after human cells were irradiated with ultraviolet light, approximately 50% of the ultraviolet-induced pyrimidine dimers were lost from the DNA.
283 citations
TL;DR: A type of DNA synthesis in mammalian cells that is stimulated by ultraviolet light has been studied by means ofRadioautography and density gradient centrifugation and the presence of bromouracil in the DNA is required before it can be demonstrated by radioautography.
Abstract: A type of DNA synthesis in mammalian cells that is stimulated by ultraviolet light has been studied by means of radioautography and density gradient centrifugation. The characteristics of this synthesis are: (a) it is not semiconservative; (b) it is enhanced by the presence of 5-bromodeoxyuridine in the DNA molecule; (c) the degree of stimulation is dose dependent; (d) there is less variability in the rate of incorporation of H3-thymidine during this synthesis than during normal DNA synthesis; (e) it occurs in cells that are not in the normal DNA synthesis phase (G1 and G2 cells). This kind of synthesis has been found in cultured cell lines from five different species; however, in some strains, the presence of bromouracil in the DNA is required before it can be demonstrated by radioautography.
281 citations