Editorial Ozone depletion: The biologic consequences The current rapid depletion of the earth's stratospheric ozone content by manmade catalysts, with an anticipated prolonged increase in irradiation of the earth's surface by high-energy, short-wavelength UVB radiation, is well documented by Brett Coldiron in the current issue of this JOURNAL (pages 653-62). Therefore, a critical question is: What are the biologic consequences that we may anticipate from this long-term, perhaps irrevocable, alteration in our ecosystem? As noted by Dr. Coldiron, the action spectrum of UVB radiation on human skin correlates closely with the absorption spectrum of cellular DNA. Indeed, there is an abundance of evidence that cellular D N A is the principal biologically relevant target of UV radiation, t-3 UV radiation produces several different lesions in DNA: in addition to the predominant photoproduct, the cyclobutane pyrimidine dimer, at least one other dipyrimidine lesion, the covalently linked pyrimidine-(6-4)-pyrimidone photoproduct, is also formed. 2-s In addition, a number of alterations in single bases in DNA, such as generation of pyrimidine hydrates 2 and thymine glycols,6 also result from UV radiation. Ofthesevarious types of lesions produced by UV radiation, the pyrimidine dimer is one of the major ones responsible for many of the pathologic effects of UV radiation, particularly mutagenesis and carcinogenesis.7, 8 The (6-4) photoproducts are mutagenic as well.9, 10 These different types of lesions in cellular DNA, whether in a plant or in human skin, are repaired by several different mechanisms. Although several of these DNA repair mechanisms have features in common, such as recognition of the damage by nuclear proteins, incision at the site of damage by an endonuclease, possibly assisted by a chromatin accessibility protein, followed by exonuclease, polymerase, and ligase activities, they can be separated by both genetic and biochemical assays. For example, a heavily mutated xeroderma pigmentosum From the Department of Laboratory Medicine and Pathology, University of Medicine and Dentistry o1"New Jersey--New Jersey Medical School. Reprint requests: Muriel W. Lambert, PhD, Department of Laboratory Medicine and Pathology, UMDNJ--New Jersey Medical School, 185 S. Orange Ave., Newark, NJ 07103. 16/1/41778

(XP) partial revertant cell line has been developed, which is defective in removal of cyclobutane pyrimidine dimers but has essentially normal repair of (6-4) photoproducts, even though the parent cell line is deficient in repair of both types of lesions.11Assays for adducts and their repair are still being developed and existing assays must be evaluated with care. This is shown in complementation group D of XP, which is also deficient in DNA repair, and in which a marked discrepancy exists between rate of cell killing by UV radiation and degree of depression of DNA repair-related, non-S phase, unscheduled DNA synthesis (UDS). 12This apparently is due, at least in part, to a greater lethal effect of (6-4) photoproducts in these cells versus a greater effect on UDS measurements by repair ofcyclobutane dimers in these ceils.12 DNA lesions cannot persist indefinitely in proliferating cells because there is no biochemical mechanism for their replication. Most of these modifications in cellular DNA are efficiently acted on by cellular enzymes so that they are repaired. However, the occasional misrepair or failure to repair a modification can lead to alterations in the sequence of bases in that portion of DNA and give rise to mutations. These mutations may cause cell death, alterations in cellular function, or neoplastic tramformation. Not only DNA repair enzymes but also those involved in DNA replication, DNA recombination, and gene expression, as well as a number of chromatin structural proteins, play important roles in these processes. Moreover, several of these enzymes normally act on DNA in a processive manner, proceeding along the DNA double helix for relatively long distances t3, t4; disruption in this progression, so that the enzyme has to function in a kinetically unfavorable, random, three-dimensional distributive mechanism, can have adverse biologic consequences. In mammalian cells, the structure of chromatin, which is organized into nucleosomes, greatly influences sites of DNA damage as well as accessibility of these sites to repair enzymes. For example, UVinduced pyrimidine dimers in DNA are located in both nucleosome core and linker regions, whereas (6-4) photoproducts are found mainly in the linker regions.IS, 16 Repair of both lesions preferentially 783

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occurs in the linker region, and, in the case of pyrimidine dimers, repair eventually is more evenly distributed over the nucleosome. ~5, 16In certain genetic diseases, such as XP, the ability of repair endonucleases to interact with UV-damaged D N A is defective when nucleosomes are present.17, 18Thus the presence of other nuclear proteins, such as the histones that make up the nucleosomes, influences the D N A repair process. As we develop methodologies for isolating and identifying the proteins involved in recognizing and repairing these different types of lesions, we will begin to unravel the complex and fascinating ways in which these repair proteins react with each other and with other chromatin proteins.18,19 In addition, the transcriptional state of chromatin can affect these repair processes. For example, D N A in many actively transcribed genes is repaired preferentially to that in inactive genes.2~ 21 There is evidence that this process is defective in the genodermatoses, XP, and Cockayne's syndrome. Many of these emerging results are of immediate relevance as we contemplate possible countermeasures to the increased D N A damage anticipated from ozone depletion. There is a growing body of evidence that some severely repair-deficient genodermatoses, such as some complementation groups of XP, may require that genes at more than one locus be defective simultaneously for the disease phenotype to be expressed.22, 23The importance of this theory, known as co-recessive inheritance, is that, if it is correct, it follows that cartier states for defective alleles for these D N A repair genes are extremely high, and these persons comprise a significant proportion of the general population. 22 This would mean that large subsets of the population would be much more sensitive to the harmful effects of UV radiation than other persons, regardless of such other ameliorating factors as degree of pigmentation. This heterogeneity would also be likely to be present in other species. This further complicates the problem of how to respond to a significant increase in UV radiation worldwide. Although a limited number of D N A repair genes have now been cloned, allowing identification of a number of analogous genes, with certain identical gene segments, in different organisms, much remains to be learned regarding ways in which these genes and their products interact. In those organisms in which DNA in chromatin is organized into nudeosomal structures, pathways involved in locat-

ing and repairing sites of damage within these structures will be much more complex than those in which nucleosomes are not present. It should b e anticipated then that D N A repair mechanisms between species will also differ, even if a number of the genes involved have partially analogous sequences. 24 Clearly, however, much more needs to be learned about these mechanisms for U V radiation-induced D N A damage and its repair if we are to meet the challenges that depletion of the ozone layer will produce in our ecosystem. Modulation of repair of U V induced lesions in D N A in humans and other species by molecular means is one possible response to this potentially critical problem.

Muriel W. Lambert, PhD Newark, New Jersey REFERENCES

1. Elad D. Photoproduets of purines. In: Wang SY, ed. Photochemistry and photobiology of nucleic acids; vol 1. Chemistry. New York; Academic Press, 1976:357-80. 2. Fisher GJ, Johns HE. Pyrimidine photodimers. In: Wang SY, ed. Photochemistryand photobiologyof nucleic acids; vol 1. Chemistry. New York: Academic Press, 1976:22594. 3. Wang SY. Pyrimidine bimoleeular photoproducts. In: Wang SY, ed. Photochemistryand photobiologyof nucleic acids; vol 1. Chemistry. New York: Academic Press, 1976:295-356. 4. Harm W. Biologicaleffects of ultraviolet radiation. London: Cambridge UniversityPress, 1980. 5. MitchellDL, N aim RS. The biologyof (6-4) photoproduct. Photochem Photobiol 1989;49:805-19. 6. DempleB, Lirm S. 5,6-Saturated thymine lesionsin DNA: production by ultravioletlight and hydrogenperoxide.Nucl Acids Res 1982;10:3781-9. 7. Hart R.W, Setlow RB, Woodhead AD. Evidence that pyrimidine dimers in DNA can giverise to tumors. Prod Nail Acad Sci U S A 1977;74:5574-8. 8. Protic-SabljicM, Tuteja N, Munson PJ, et al. UV light-induced cyclobutane pyrimidine dimers are mutagenic in mammalian cells. Molec Cell Biol 1986;6:3349-56. 9. Franklin W, DoetschP, Haseltine W. Structural deterrninatxon of the ultravioletlight-induced thymine-cytosinepyrimidine-pyrimidone (6-4) photoproduct. Nucl Acids Res 1985;13:5317-25. 10. BrashDE, Seetharam S, Kraemer KH, et al. Photoproduet frequencyis not the major determinant of UV base substitution hot spotsor coldspotsin human ceils.Proc Natl Acad Sci U S A 1987;84:3782-6. 11. CleaverJE, CortesF, Lutze LH, et al. UniqueDNArepair properties of a xeroderma pigmentosum revertant. Molee Cell Biol 1987;7:3353-7. 12. JohnsonRT, SquiresS. The XPD complementationgroup: insights into xeroderma pigmentosum, Cockayne's syndrome and trichothiodystrophy. Murat Res 1992;273:97118. 13. yon Hippel PH, Berg OG. Facilitated target location in biological systems. J Biol Chem 1989;264:675-8. 14. DowdDR, Lloyd RS. Biologicalsignificanceof facilitated

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diffusion in protein-DNA interactions. J Biol Chem 1990;265:3424-31. Gale JM, Nissen KA, Smerdon MJ. UV-induced formation of pyrimidine dimers in nucleosome core DNA is strongly modulated with a period of 10.3 bases. Proc Natl Acad Sei U S A 1987;84:6644-8. Mitchell DL, Nguyen TD, Cleaver JE. Nonrandom induction of pyrimidine-pyrimidone (6-4) photo-products in ultraviolet-irradiated human ehromatin. J Biol Chem 1990;265:5353-6. Lambert MW, Parrish DD. Modulation of activity of human chromatin-associated endonucleases on damaged D N A by nucleosome structure. In: Lambert MW, Laval J, eds. D N A repair mechanisms and their biological implications in mammalian cells. New York: Plenum, 1989:295324. Parrish DD, Lambert WC, Lambert MW. Xeroderma pigmentosum endonuclease complexes show reduced activity on and atFanity for psoralen cross-linked nucleosomal DNA. Mutat Res 1992;273:157-70.

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19. Tsongalis GJ, Lambert WC, Lambert MW. Electroporation of normal human D N A endonucleases into xeroderma pigmentosum cells corrects their DNA repair defect. Careinogenesis 1990;11:499-503. 20. Bohr VA. Gene specific DNA repair. Carcinogenesis 1991 ;12:1983-92. 21. Link CJ Jr, Burt RK, Bohr VA. Gene-specific repair of DNA damage induced by UV irradiation and cancer chemotherapeutics. Cancer Cells 1991;3:427-36. 22. Lambert WC, Lambert MW. Co-recessive inheritance: a modal for DNA repair and other surveillance genes in higher eukaryotes. Mutat Res 1992;273:179-92. 23. Vuillanme M, Daya-Grosjean L, Vincens P, et al. Striking differences in cellular catalase activity between two DNA repair-deficient diseases: xeroderma pigmentosum and trichothiodystrophy. Carcinogenesis 1992;13:321-8. 24. Hoeijmakers JHJ. How relevant is theEscherichia coilUvr ABC model for excision repair in eukaryotes? J Cell Sei 1991 ;I 00:687-91.

Ozone depletion: the biologic consequences.

Editorial Ozone depletion: The biologic consequences The current rapid depletion of the earth's stratospheric ozone content by manmade catalysts, with...
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