Abstract
There have been many attempts to analyze the complex relationships between measured DNA repair levels in mammalian cells and various biological end-points such as survival, mutagenesis, and transformation. In such studies the repair proficiency has been assumed to be uniform throughout the genome and, in fact, cell population homogeneity is also generally assumed. However, it is quite likely that DNA damage in some domains of the genome is processed more efficiently than in others and that such heterogeneity in repair would result in corresponding differences in the responses seen for particular biological effects. The genome includes many different functional classes of DNA of which some are “silent” (e.g., repetitive sequences in heterochromatin, unexpressed genes) while others are active (e.g., expressed genes, elements required for the translation machinery, and various regulatory regions). The consequences of unrepaired or misrepaired damage in DNA will most certainly depend upon the precise location of the damage with respect to these functional classes. This fact is well-documented at the nucleotide sequence level in bacteria by correlations of the spectrum of particular lesions with “hot spots” for mutagenesis. However, we have obtained little information on the specificity of the mutagenic response in relation to damage and repair in mammalian systems, analyzed at the various levels of genomic organization. Differences in the repair response to damage in selected genomic regions may account for some of the profound differences seen in the carcinogenic response in different tissues or when different organisms are compared. Therefore, it may be important to understand the “fine structure” of DNA repair in mammalian genomes in order to assess carcinogenic risks.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
P. C. Hanawalt, P.K. Cooper, A.K. Ganesan and C.A. Smith, DNA repair in bacteria and mammalian cells, Annu.Rev.Biochem. 48: 783–836 (1979).
D. E. Pettijohn, and P.C. Hanawalt, Evidence for repair replication of ultraviolet damaged DNA in bacteria, J.Mol.Biol. 9: 395–410 (1964).
C. A. Smith, P. K. Cooper, and P. C. Hanawalt, Measurement of repair replication by equilibrium sedimentation, in E. C. Friedberg and P.C. Hanawalt (Eds.), DNA Repair: A Laboratory Manual of Research Procedures. Marcel Dekker Inc., Vol I, part B 289–305 (1981).
J. E, Cleaver, and G. H. Thomas, Measurement of unscheduled synthesis by autoradiography, in E. C. Friedberg and P. C. Hanawalt (Eds.), DNA Repair: A Laboratory Manual of Research Procedures Vol I, part B pp.277–287 (1981).
A. K. Ganesan, C. A. Smith and A. A. van Zeeland, Measurement of the pyrimidine dimer content of DNA in permeabilized bacterial or mammalian cells with endonuclease V of bacteriophage T4, in E. C. Friedberg and P. C. Hanawalt (Eds.), DNA Repair: A Laboratory Manual of Research Procedures. Marcel Dekker Inc., Vol 1, part A, pp.89–97 (1980).
R. B. Setlow and J. D. Regan, Measurement of repair synthesis by photolysis of bromouracil, in E. C. Friedberg and P. C. Hanawalt (Eds.), DNA Repair: A Laboratory Manual of Research Procedures. Marcel Dekker Inc., Vol 1, part B. pp.307–318 (1981).
A. S. Leadon and P. C. Hanawalt, Differential repair of DNA damage in specific nucleotide sequences in mammalian cells, Radiation Research Society Abstracts Gg-6 (1985).
S. M. Cohn, and M.W. Lieberman, The use of antibodies to 5-bromo-2′-deoxyuridine for the isolation of DNA sequences containing excision-repair sites, J. Biol. Chem. 259: 12456–12462 (1984).
S. M. Cohn, and M.W. Lieberman, The distribution of DNA excision-repair sites in human diploid fibroblasts following ultraviolet irradiation, J. Biol. Chem. 259: 12463–12469 (1984).
T. R. Irvin, and GL N. Wogan, Quantitation of aflatoxin B1 adduction within the ribosomal RNA gene sequences of rat liver DNA, Proc. Natl. Acad, Sci. U.S.A. 81: 664–668 (1984).
L. V. Mayne, Inhibitors of DNA synthesis (aphidicolin and araC/HU) prevent the recovery of RNA synthesis after UV-irradiation, Mutat. Res. 131: 187–191 (1984).
M. W. Lieberman and M.C. Poirier, Intragenomal distribution of DNA repair synthesis: repair in satellite and mainband DNA in cultured mouse cells, Proc. Natl. Acad. Sci. U.S.A. 71: 2461–2465 (1984).
M. E. Zolan, G. A. Cortopassi, C. A. Smith, and P. C. Hanawalt, Deficient repair of chemical adducts in alpha DNA of monkey cells, Cell 28613–619 (1982).
V. A. Bohr, C. A. Smith, D. S. Okumoto, and P. C. Hanawalt, DNA repair in an active gene: removal of pyrimidine dimers from the DHFR gene of CHO cells is much more efficient than in the genome overall, Cell 40: 359–369 (1985).
J. N. Mansbridge, and P.C. Hanawalt, Domain-limited repair of DNA in ultraviolet irradiated fibroblasts from xeroderma pigmentosum complementation group C, in E.C. Friedberg and B.R. Bridges (Eds.) Cellular Responses to DNA Damage. UCLA Symp on Mol. and Cellu. Biol. Vol II, Alan R. Liss, Inc. New York, pp.195–207 (1983).
S. A. Leadon and P. C Hanawalt, Monoclonal antibody to DNA containing thymine glycol, DNA Repair Reports: Mutation Res 112: 191–200 (1983).
S. A. Leadon, M. E. Zolan, and P. C. Hanawalt, Restricted repair of aflatoxin B1 induced damage in alpha DNA of monkey cells, Nucl. Acids Res. 11: 5675–5689 (1983).
S. A. Leadon, and P. C Hanawalt, Ultraviolet irradiation of monkey cells enhances the repair of DNA adducts in alpha DNA, Carcinogenesis 5: 1505–1510 (1984).
M. E. Zolan, C. A. Smith, and P. C. Hanawalt, Formation and repair of furocoumarin adducts in alpha DNA and bulk DNA of monkey cells, Biochemistry 23: 63–69 (1984).
S. A. Leadon, P. A. Amstad, and P. A. Cerutti, Repair and expression of aflatoxin B1-induced DNA damage, in A. Castellani (Ed), Proc NATO Adv. Study Inst. on use of human cells for assessment of risk from physical and chemical agents. Plenum Press, 60: 105–117 (1983).
A. Sarasin, C. A. Smith, and P. C. Hanawalt, Repair of DNA in human cells after treatment with activated aflatoxin B1, Cancer Res. 37: 1786–1793 (1977).
J. E. Arrand, and A. M. Murray, Benzpyrene groups bind preferentially to the DNA of active chromatin in lung cells, Nucl. Acids Res. 10: 1547–1555 (1982).
K. Nose, and O. Nikaido, Transcriptionally active and inactive genes are similarly modified by chemical carcinogens and X-ray in normal human fibroblasts, Biochim. Biophys. Acta 781: 273–278 (1984).
A. Ganesan, G. Spivak, and P.C. Hanawalt, Expression of DNA repair genes in mammalian cells, in P. Nagley, A. W. Linnane, W. J. Peacock, and J. A. Pateman (Eds.), Manipulation and Expression of Genes in Eukaryotes. Academic Press, Sidney, Australia, pp.45–54 (1983).
P. C. Hanawalt, J. Kaye, C. A. Smith, and M. Zolan, Cellular responses to psoralen adducts in DNA, in Psoralens — in Cosmetics and Dermatology Pergamon Press, pp.133–142 (1982).
T. Lindahl, DNA repair enzymes, Annu. Rev. Biochem 51: 61–87 (1982).
J. H. Robbins, K. H. Kraemer, M. A. Lutzner, B. W. Festoff, and H. G. Coon, Xeroderma Pigmentosum: An inherited disease with sun sensitivity, multiple cutaneous neoplasms, and abnormal DNA repair, in Annals of Internal Medicine 80: 221–248 (1974).
K. Tanaka, S. Sekiguchi, and Y. Oka da, Restoration of ultraviolet-induced unscheduled DNA synthesis of xeroderma pigmentosum cells by the concomitant treatment with bacteriophage T4 endonuclease V and HVJ (Sendai virus), Proc. Natl. Acad, Sci. USA 72: 4071–4075 (1975).
K. Tanaka, H. Hayakawa, M. Sekiguchi, and Y. Okada, Specific action of T4 endonuclease V on damaged DNA in xeroderma pigmentosum cells in vivo. Proc. Natl. Acad. Sci. USA 74: 2958–2962 (1977).
G. Ciarrocchi, and S Linn, A cell-free assay measuring repair DNA synthesis in human fibroblasts, Proc Natl. Acad. Sci. USA 75: 1887–1891 (1978).
C.A. Smith, and P.C. Hanawalt, Phage T4 endonuclease V stimulates DNA repair replication in isolated nuclei from ultraviolet-irradiated human cells, including xeroderma pigmentosum fibroblasts, Proc. Natl. Acad. Sci. USA 75: 2598–2606 (1978).
K. Mortlemans, E.C. Friedberg, H. Slor, G. Thomas, and J.E. Cleaver, Defective thymine dimer excision by cell-free extracts of xeroderma pigmentosum cells, Proc. Natl. Acad. Sci. USA 73: 2757–2761 (1976).
Y. Fujiwara and Y. Kano, Characteristics of thymine dimer excision from xeroderma pigmentosum chromatin, in E. C. Friedberg and B. A. Bridges (Eds.) Cellular Responses to DNA Damage. UCLA Symp. on Mol. and Cellu.Biol. Vol II, Alan R. Liss, Inc. New York, pp. 215–224, (1983).
L. H. F. Mullenders, A. C. van Kesteren, C. J. M. Bussmann, A. A. van Zeeland, and A. T. Natarajan, Preferential repair of nuclear matrix associated DNA in xeroderma pigmentosum complementation group C, Mutation Res. 141: 75–82 (1984).
V. Bohr and P. Hanawalt, Factors that affect the initiation of excision-repair in chromatin, in A. Collins, C. S. Downes, and R. T. Johnson (Eds), DNA Repair and its Inhibition. IRL Press, Oxford pp.109–125 (1984).
UK. Gordon and W. A. Hasel tine, Comparison of the cleavage of pyrimidine dimers by the bacteriophage T4 and Micrococcus luteus UV-specific endonucleases, J.Biol.Chem. 255: 12047–12050 (1980).
R. J. Wilkins and R. W. Hart, Preferential DNA repair in human cells, Nature 247: 35–36 (1974).
G. J. Kantor and R. B. Setlow, Rate and extent of DNA repair in nondividing human diploid fibroblasts, Cancer Res. 41: 819–825 (1981).
M. E. Zolan, C. A. Smith, N. M. Calvin, and P. C. Hanawalt, Rearrangement of mammalian chromatin structure following excision repair, Nature 299: 462–463 (1982).
C. J. Marshall, K. H. Vousden, and D. H. Phillips, Activation of c-Ha-ras-1 proto-oncogene by in vitro modification with a chemical carcinogen, benzo(a)pyrene diol-epoxide, Nature 310: 586–589 (1984).
R. Ben-Ishai and L. Peleg, Excision-repair in primary cultures of mouse embryo cells and its decline in progressive passages and established cell lines, in P. C. Hanawalt, and R. B. Setlow (Eds.) Molecular Mechanisms for Repair of DNA Part B Plenum Press, New York, pp.607–610 (1975).
T. Yagi, DNA repair ability of cultured cells derived from mouse embryos in comparison with human cells, Mutation Res. 96: 89–98 (1982).
G. C. Elliott and R. T. Johnson, DNA repair in mouse embryo fibroblasts — I. Decline in ultraviolet-induced incision rate accompanies cell transformation, J. Cell Sci. 60: 267–288 (1983).
C. Wu and W. Li, Evidence for higher rates of nucleotide substitution in rodents than in man, Proc. Natl. Acad. Sci. USA 82: 1741–1745 (1985).
M. A. Goldman, G. P. Holmquist, M. C. Gray, L. A. Caston, and A. Nag, Replication timing of genes and middle repetitive sequences, Science 224: 686–692 (1984).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1986 Plenum Press, New York
About this chapter
Cite this chapter
Hanawalt, P.C. (1986). Intragenomic Heterogeneity in DNA Damage Processing: Potential Implications for Risk Assessment. In: Simic, M.G., Grossman, L., Upton, A.C., Bergtold, D.S. (eds) Mechanisms of DNA Damage and Repair. Basic Life Sciences, vol 189. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-9462-8_51
Download citation
DOI: https://doi.org/10.1007/978-1-4615-9462-8_51
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4615-9464-2
Online ISBN: 978-1-4615-9462-8
eBook Packages: Springer Book Archive