Medical Background: Human DNA Damage Recognition and Processing Disorders

  • Hanspeter Naegeli
Part of the Molecular Biology Intelligence Unit book series (MBIU)


If left uncorrected, DNA damage poses multiple threats to the proper functioning of DNA. First, many DNA lesions cause cytotoxic cell death by interfering with essential transactions such as transcription or DNA replication.1,2 Second, DNA lesions induce lethality by triggering pathways of programmed cell death (apoptosis).3,4 Third, cells that survive are subject to permanent changes in the nucleotide sequence, or genetic code, of DNA. This mutagenic response is due to the increased probability that errors occur upon replication of damaged templates.5,6 Multiple DNA damage processing pathways have been identified in mammalian cells, all of which are able to modulate the cytotoxic, apoptotic or mutagenic effects of DNA lesions. Among these pathways, DNA repair acts as a key line of defense to remove injuries to DNA and increase cell survival by allowing resumption of transcription or replication. DNA repair processes also minimize the mutagenic consequences of DNA damage, thereby preventing the accumulation of mutations at critical positions in DNA and reducing the incidence of cancer or inherited diseases.1,7,8


Excision Repair Nucleotide Excision Repair Xeroderma Pigmentosum Ataxia Telangiectasia Cyclobutane Pyrimidine Dimer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Friedberg EC, Walker GC, Siede W. DNA Repair and Mutagenesis. Washington, D.C.: American Society for Microbiology, 1995.Google Scholar
  2. 2.
    Grisham JW, Greenberg DS, Kaufman DG et al. Cycle-related toxicity and transformation in 10T1/2 cells treated with N-methyl-N′-nitro-N-nitroso-guanidine. Proc Natl Acad Sci USA 1980; 77:4813–4817.Google Scholar
  3. 3.
    Chu G. Cellular responses to cisplatin. J Biol Chem 1994; 269:787–790.Google Scholar
  4. 4.
    Williams GT, Smith CA. Molecular regulation of apoptosis: genetic controls on cell death. Cell 1993; 74:777–779.Google Scholar
  5. 5.
    Strauss BS. The “A rule” of mutagen specificity: a consequence of DNA polymerase bypass of non-instructional lesions? BioEssays 1991; 13:79–84.Google Scholar
  6. 6.
    McBride TJ, Preston BD, Loeb LA. Mutagenic spectrum resulting from DNA damage by oxygen radicals. Biochemistry 1991; 30:207–213.Google Scholar
  7. 7.
    Sancar A. Mechanisms of DNA excision repair. Science 1994; 266:1954–1956.Google Scholar
  8. 8.
    Hoeijmakers JHJ. Human nucleotide excision repair syndromes: molecular clues to unexpected intricacies. Europ J Cancer 1994; 30A:1912–1921.Google Scholar
  9. 9.
    Keiner A. Effect of visible light on the recovery of Streptomyces griseus conidea from ultra-violet irradiation injury. Proc Natl Acad Sci USA 1949; 35:73–79.Google Scholar
  10. 10.
    Rupert CS, Goodgal SH, Herriott RM. Photoreactivation in vitro of ultravioletinactivated transforming factor in Haemophilus influenzae. J Gen Physiol 1958; 41:451–471.Google Scholar
  11. 11.
    Hanawalt PC. Evolution and concepts in DNA repair. Environ Mol Mutagen 1994; 23 (Suppl 24):78–85.Google Scholar
  12. 12.
    Li YF, Kim ST, Sancar A. Evidence for lack of DNA photoreactivating enzyme in humans. Proc Natl Acad Sci USA 1993; 90:4389–4393.Google Scholar
  13. 13.
    Sutherland BM, Bennett PV. Human white blood cells contain cyclobutyl pyrimidine dimer photolyase. Proc Natl Acad Sci USA 1995; 92:9732–9736.Google Scholar
  14. 14.
    Pegg AE, Byers TL. Repair of DNA containing O 6-alkylguanine. FASEB J 1992; 6:2302–2310.Google Scholar
  15. 15.
    Setlow RB, Carrier WL. The disappearance of thymine dimers from DNA: an error-correcting mechanism. Proc Natl Acad Sci USA 1963; 51:226–231.Google Scholar
  16. 16.
    Boyce RP, Howard-Flanders P. Release of ultraviolet light-induced thymine dimers from DNA in E. coli K-12. Proc Natl Acad Sci USA 1964; 51:293–300.Google Scholar
  17. 17.
    Yajima H, Takao M, Yasuhira S et al. A eukaryotic gene encoding an endonuclease that specifically repairs DNA damaged by ultraviolet light. EMBO J 1995; 14:2393–2399.Google Scholar
  18. 18.
    Bowman KK, Sidik K, Smith CA et al. A new ATP-independent DNA endonclease from Schizosaccharomyces pombe that recognizes cyclobutane pyrimidine dimers and 6-4 photoproducts. Nucleic Acids Res 1994; 22:3026–3032.Google Scholar
  19. 19.
    Dunderdale HJ, West SC. Recombination genes and proteins. Curr Opin Genet Dev 1994; 4:221–228.Google Scholar
  20. 20.
    Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science 1989; 246:629–634.Google Scholar
  21. 21.
    Naegeli H. Roadblocks and detours during DNA replication: mechanisms of mutagenesis in mammalian cells. BioEssays 1994; 16:557–564.Google Scholar
  22. 22.
    Lindahl T. Instability and decay of the primary structure of DNA. Nature 1993; 362:709–715.Google Scholar
  23. 23.
    Sancar A, Franklin KA, Sancar GB. Escherichia coli DNA photolyase stimulates UvrABC excision nuclease in vitro. Proc Natl Acad Sci USA 1984; 81:7397–7401.Google Scholar
  24. 24.
    Duckett DR, Drummond JT, Murchie AIH et al. Human MutSa recognizes damaged DNA base pairs containing O 6-methylguanine, O 4-methylthymine, or the cisplatin-d(GpG) adduct. Proc Natl Acad Sci USA 1996; 93:6443–6447.Google Scholar
  25. 25.
    Turchi JJ, Henkels K. Human Ku auto-antigen binds cisplatin-damaged DNA but fails to stimulate human DNA-acti-vated protein kinase. J Biol Chem 1996; 271:13861–13867.Google Scholar
  26. 26.
    Schiestl RH, Prakash S. RADIO, an excision repair gene of Saccharomyces cerevisiae, is involved in the RAD1 pathway of mitotic recombination. Mol Cell Biol 1990; 10:2485–2491.Google Scholar
  27. 27.
    Adamczewski JP, Rossignol M, Tassan J-P et al. MAT1, cdk7 and cyclin H form a kinase complex which is UV-light sensitive upon association with TFIIH. EMBO J 1996; 15:1877–1884.Google Scholar
  28. 28.
    Wang XW, Yeh H, Schaeffer L et al. p53 modulation of TFIIH-associated nucle-otide excision repair activity. Nature Genetics 1995; 10:188–195.Google Scholar
  29. 29.
    Schaeffer L, Roy R, Humbert S et al. DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science 1993; 260:58–63.Google Scholar
  30. 30.
    Coverley D, Kenny MK, Munn M et al. Requirement for the replication protein SSB in human DNA excision repair. Nature 1991; 349:538–541.Google Scholar
  31. 31.
    Stürzbecher H-W, Donzelmann B, Henning W et al. p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction. EMBO J 1996; 15:1992–2002.Google Scholar
  32. 32.
    Goldmacher VS, Cuzick RA, Thilly WG. Isolation and partial characterization of human cell mutants differing in sensitivity to killing and mutation by methylnitrosourea and N-methyl-N′-nitro-N-nitrosoguanidine. J Biol Chem 1986; 261:12462–12471.Google Scholar
  33. 33.
    Hawn MT, Umar A, Carethers JM et al. Evidence for a connection between the mismatch repair system and G2 cell cycle checkpoint. Cancer Res 1995; 55:3721–3725.Google Scholar
  34. 34.
    Mellon I, Rajpal D, Koi M et al. Transcription-coupled repair deficiency and mutations in human mismatch repair genes. Science 1996; 272:557–560.Google Scholar
  35. 35.
    Arlett CF. Mutagenesis in repair-deficient human cell strains. In: Alacevic M, ed. Progress in Environmental Mutagenesis. Amsterdam: Elsevier, 1980:161–174.Google Scholar
  36. 36.
    Cleaver JE. Defective repair replication of DNA in xeroderma pigmentosum. Nature 1968; 218:652–656.Google Scholar
  37. 37.
    Kraemer KH, Levy DD, Parris CN et al. Xeroderma pigmentosum and related disorders: examining the linkage between defective DNA repair and cancer. J Invest Dermatol 1994; 103:96–101.Google Scholar
  38. 38.
    Kraemer KH. Xeroderma pigmentosum. In: Demis DJ, Dobson RL, McGuire J, eds. Clinical Dermatology. Hagerstown: Harper and Row, 1980:1–33.Google Scholar
  39. 39.
    Cleaver JE, Kraemer KH. Xeroderma pigmentosum. In: Criver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Human Disease. 6th ed. New York: McGraw Hill, 1989:2949–2971.Google Scholar
  40. 40.
    Kraemer KH, Lee M-M, Andrews AD et al. The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer. Arch Dermatol 1994; 130:1018–1021.Google Scholar
  41. 41.
    English JS, Swerdlow AJ. The risk of malignant melanoma, internal malignancy and mortality in xeroderma pigmentosum patients. Br J Dermatol 1987; 117:457–461.Google Scholar
  42. 42.
    Scotto J, Fears TR, Fraumeni JF. Incidence of non-melanoma skin cancer in the United States. Bethesda, Md: US Dept of Health and Human Services 1982; NIH publication No. 82-2433.Google Scholar
  43. 43.
    Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum. Cutaneous, ocular and neurological abnormalities in 830 published cases. Arch Dermatol 1987; 123:241–250.Google Scholar
  44. 44.
    Stich HF, San RHC, Kawazoe Y. Increased sensitivity of xeroderma pigmentosum cells to some chemical carcinogens and mutagens. Mutat Res 1973; 17:127–137.Google Scholar
  45. 45.
    Maher VM, Birch N, Otto JR et al. Cytotoxicity of carcinogenic aromatic amides in normal and xeroderma pigmentosum fibroblasts with different DNA repair capabilities. J Natl Cancer Inst 1975; 54:1287–1294.Google Scholar
  46. 46.
    Maher VM, McCormick JJ. Effect of DNA repair on the cytotoxicity and mutagenicity of UV irradiation and of chemical carcinogens in normal and xeroderma pigmentosum cells. In: Yuhas JM, Tennant RW, Regan JD, eds. Biology of Radiation Carcinogens. New York: Raven Press, 1976:129–145.Google Scholar
  47. 47.
    Maher VM, Ouellette LM, Curren RD et al. Frequency of ultraviolet light-induced mutations is higher in xeroderma pigmentosum variant cells than in normal human cells. Nature 1976; 261:593–595.Google Scholar
  48. 48.
    Dumaz N, Drougard C, Sarasin A et al. Specific UV-induced mutation spectrum in the p53 gene of skin tumors from DNA-repair-deficient xeroderma pigmentosum patients. Proc Natl Acad Sci USA 1993; 90:10529–10533.Google Scholar
  49. 49.
    Brash DE, Rudolph JA, Simon JA et al. A role for sunlight in skin cancer: UV-induced p 53 mutations in squamous cell carcinoma. Proc Natl Acad Sci USA 1991; 88:10124–10128.Google Scholar
  50. 50.
    Lehmann AR, Kirk-Bell S, Arlett CF et al. Xeroderma pigmentosum cells with normal levels of excision repair have a defect in DNA synthesis after UV-irra-diation. Proc Natl Acad Sci USA 1975; 72:219–223.Google Scholar
  51. 51.
    Stefanini M, Lagomarsini P, Arlett CF et al. Xeroderma pigmentosum (complementation group D) mutation is present in patients affected by trichothiodystrophy with photosensitivity. Human Genet 1986; 74:107–112.Google Scholar
  52. 52.
    Stefanini M, Lagomarsini P, Giliani S et al. Genetic heterogeneity of the excision repair defect associated with trichothiodystrophy. Carcinogenesis 1993; 14:1101–1105.Google Scholar
  53. 53.
    Stefanini M, Vermeulen W, Weeda G et al. A new nucleotide-excision-repair gene associated with the disorder trichothiodystrophy. Am J Hum Genet 53:817-821.Google Scholar
  54. 54.
    Johnson RT, Squires S. The XPD complementation group. Insights into xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Mutat Res 1992; 273:97–118.Google Scholar
  55. 55.
    Broughton BC, Steingrimsdottir H, Weber CA et al. Mutations in xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy. Nature Genet 1994; 7:189–194.Google Scholar
  56. 56.
    Takayama K, Salazar EP, Broughton B et al. Defects in the DNA repair and transcription gene ERCC2(XPD) in trichothiodystrophy. Am J Hum Genet 1996; 58:263–270.Google Scholar
  57. 57.
    Itin PH, Pittelkow MR. Trichothiodystrophy: review of sulfur-deficient brittle hair syndromes and association with the ectodermal dysplasias. J Am Acad Dermatol 1990; 22:705–717.Google Scholar
  58. 58.
    Kleijer WJ, Beemer FA, Boom BW. Intermittent hair loss in a child with PIBI(D)S syndrome and trichothiodystrophy with defective DNA repair-xeroderma pigmentosum group D. Am J Med Genet 1994; 52:227–230.Google Scholar
  59. 59.
    Van Neste D, Caulier B, Thomas P et al. PIBIDS: Tay’s syndrome and xeroderma pigmentosum. J Am Acad Dermatol 1985; 12:372–373.Google Scholar
  60. 60.
    Sarasin A, Blanchet-Bardot C, Renault G et al. Prenatal diagnosis in a subset of trichothiodystrophy patients defective in DNA repair. Br J Dermatol 1992; 127:485–491.Google Scholar
  61. 61.
    Mazdak C, Armier J, Stary A et al. UV-induced mutations in a shuttle vector replicated in repair deficient trichothiodystrophy cells differ with those in genetically-related cancer prone xeroderma pigmentosum. Carcinogenesis 1993; 14:1255–1260.Google Scholar
  62. 62.
    Marionnet C, Benoit A, Benhamou S. Characteristics of UV-induced mutation spectra in human XP-D/ERCC2 gene-mutated xeroderma pigmentosum and trichothiodystrophy cells. J Mol Biol 1995; 252:550–562.Google Scholar
  63. 63.
    Lehmann AR. Cockayne’s syndrome and trichothiodystrophy: defective repair without cancer. Cancer Rev 1987; 7:82–103.Google Scholar
  64. 64.
    Vuillaume M, Daya-Grosjean L, Vincens P et al. Striking differences in cellular cata-lase activity between two DNA repair-deficient diseases: xeroderma pigmentosum and trichothiodystrophy. Carcinogenesis 1992; 13:321–328.Google Scholar
  65. 65.
    Norris PG, Limb GA, Hamblin AS et al. Impairment of natural-killer-cell activity in xeroderma pigmentosum. N Engl J Med 1988; 319:1668–1669.Google Scholar
  66. 66.
    Morison WL, Bucana C, Hashem N et al. Impaired immune function in patients with xeroderma pigmentosum. Cancer Res 1985; 45:3929–3931.Google Scholar
  67. 67.
    Wysenbeek AJ, Weiss H, Duczyminer-Kahana M et al. Immunologic alterations in xeroderma pigmentosum patients. Cancer 1986; 58:219–221.Google Scholar
  68. 68.
    Kripke ML, Cox PA, Alas LG et al. Pyrimidine dimers in DNA initiate systemic immunosuppression in UV-irradiated mice. Proc Natl Acad Sci USA 1992; 89:7516–7520.Google Scholar
  69. 69.
    Nishigori C, Yarosh DB, Ullrich S et al. Evidence that DNA damage triggers inter-leukin 10 cytokine production in UV-irradiated murine keratinocytes. Proc Natl Acad Sci USA 1996; 93:10354–10359.Google Scholar
  70. 70.
    Vermeulen W, van Vuuren AJ, Chipoulet L et al. Three unusual repair deficiencies associated with transcription factor BTF2 (TFIIH). Evidence for the existence of a transcription syndrome. Cold Spring Harbor Symp Quant Biol 1994; 59:317–329.Google Scholar
  71. 71.
    Guzder SN, Sung P, Prakash S. Lethality in yeast of trichothiodystrophy (TTD) mutations in the human xeroderma pigmentosum group D gene. J Biol Chem 1995; 270:17660–17663.Google Scholar
  72. 72.
    Friedberg EC, Bardwell AJ, Bardwell L et al. Transcription and nucleotide excision repair-reflections, considerations and recent biochemical insights. Mutat Res 1994; 307:5–14.Google Scholar
  73. 73.
    Mullenders LHF, Sakker RJ, van Hoffen A et al. Genomic heterogeneity of UV-induced repair: relationship to chromatin structure and transcrip-tional activity. In: Bohr VA, Wasserman K, Kraemer KH, eds. DNA Repair Mechanisms. Copenhagen: Munksgaard Press, 1992:247–254.Google Scholar
  74. 74.
    van Hoffen A, Natarajan AT, Mayne LV et al. Deficient repair of the transcribed strand of active genes in Cockayne’s syndrome. Nucleic Acids Res 1993; 21:5890–5895.Google Scholar
  75. 75.
    Venema J, Mullenders LH, Natarajan AT et al. The genetic defect in Cockayne syndrome is associated with a defect in repair of UV-induced DNA damage in transcriptionally active DNA. Proc Natl Acad Sci USA 1990; 87:4707–4711.Google Scholar
  76. 76.
    Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1936; 11:1–8.Google Scholar
  77. 77.
    Cockayne EA. Dwarfism with retinal atrophy and deafness. Arch Dis Child 1946; 21:52–54.Google Scholar
  78. 78.
    Cantani A, Bamonte G, Bellioni P et al. Rare syndromes. I. Cockayne syndrome: a review of the 129 cases so far reported in the literature. Riv Eur Sci Med Pharmacol 1987; 9:9–17.Google Scholar
  79. 79.
    Nance MA, Berry SA. Cockayne syndrome: review of 140 cases. Am J Med Genet 1992; 42:68–84.Google Scholar
  80. 80.
    Schmickel RD, Chu EHY, Trosko JE et al. Cockayne syndrome: a cellular sensitivity to ultraviolet light. Pediatrics 1977; 60:135–139.Google Scholar
  81. 81.
    Andrews AD, Barrett SF, Yoder FW et al. Cockayne’s syndrome fibroblasts have increased sensitivity to ultraviolet light but normal rates of unscheduled DNA synthesis. J Invest Dermatol 1978; 70:237–239.Google Scholar
  82. 82.
    Hoar DI, Waghorne C. DNA repair in Cockayne syndrome. Am J Hum Genet 1978; 30:590–601.Google Scholar
  83. 83.
    Wade MH, Chu EHY. Effects of DNA damaging agents on cultured fibroblasts derived from patients with Cockayne syndrome. Mutat Res 1979; 59:49–60.Google Scholar
  84. 84.
    Marshall RR, Arlett CF, Harcourt SA. Increased sensitivity of cell strains from Cockayne’s syndrome to sister chromatid exchange induction and cell killing by UV light. Mutat Res 1980; 69:107–112.Google Scholar
  85. 85.
    Ahmed FE, Setlow RB. Excision repair in ataxia telangiectasia, Fanconi’s anemia, Cockayne syndrome, and Bloom’s syndrome after treatment with ultraviolet radiation and N-acetoxy-2-acetylamino-fluorene. Biochim Biophys Acta 1978; 521:805–817.Google Scholar
  86. 86.
    Mayne LV, Lehmann AR. Failure of RNA synthesis to recover after UV irradiation: an early defect in cells from individuals with Cockayne’s syndrome and xeroderma pigmentosum. Cancer Res 1982; 42:1473–1478.Google Scholar
  87. 87.
    Lehmann AR, Kirk-Bell S, Mayne L. Abnormal kinetics of DNA synthesis in ultraviolet light-irradiated cells from patients with Cockayne’s syndrome. Cancer Res 1979; 39:4237–4241.Google Scholar
  88. 88.
    Mayne LV, Lehmann AR, Waters R. Excision repair in Cockayne syndrome. Mutat Res 1982; 106:179–189.Google Scholar
  89. 89.
    Tanaka K, Kawai KY, Kumahara Y et al. Genetic complementation groups in Cockayne syndrome. Som Cell Genet 1981; 7:445–456.Google Scholar
  90. 90.
    Vermeulen W, Jaeken J, Jaspers NG et al. Xeroderma pigmentosum complementation group G associated with Cockayne syndrome. Am J Human Genet 1993; 53:185–192.Google Scholar
  91. 91.
    Itoh T, Cleaver JE, Yamaizumi M. Cockayne syndrome complementation group B associated with xeroderma pigmentosum phenotype. Hum Genet 1996; 97:176–179.Google Scholar
  92. 92.
    Troelstra C, Odijk H, de Wit J et al. Molecular cloning of the human DNA excision repair gene ERCC-6. Mol Cell Biol 1990; 10:5806–5813.Google Scholar
  93. 93.
    Troelstra C, Van Gool A, De Wit J et al. ERCC6, a member of a subfamily of putative helicases, is involved in Cockayne’s syndrome and preferential repair of active genes. Cell 1992; 71:1–15.Google Scholar
  94. 94.
    Henning KA, Li L, Iyer N et al. The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH. Cell 1995; 82:555–564.Google Scholar
  95. 95.
    Neer EJ, Schmidt CJ, Nambudripad R et al. The ancient regulatory-protein family of WD-repeat proteins. Nature 1994; 371:297–300.Google Scholar
  96. 96.
    Fanconi G. Familial constitution pan-myelocytopathy, Fanconi’s anemia (F.A.).I. Clinical aspects. Semin Hematol 1967; 4:233–240.Google Scholar
  97. 97.
    Schroeder TM, Tigen D, Kruger J et al. Formal genetics of Fanconi’s anemia. Hum Genet 1976; 32:257–288.Google Scholar
  98. 98.
    Auerbach AD. Fanconi anemia and leukemia: tracking the genes. Leukemia 1992; 6 (Suppl 1):1–4.Google Scholar
  99. 99.
    Auerbach AD. Leukemia and preleukemia in Fanconi anemia patients: a review of the literature and report of the international Fanconi Anemia Registry. Cancer Genet Cytogenet 1991; 51:1–12.Google Scholar
  100. 100.
    Schroeder TM, Anschütz F, Knopp A. Spontane Chromosomenaberrationen bei familyärer Panmyelopathie. Humangenetik 1964; 1:194–196.Google Scholar
  101. 101.
    Sasaki MS, Tonomura A. A high susceptibility of Fanconi’s anemia to chromosome breakage by DNA cross linking agents. Cancer Res 1973; 33:1829–1836.Google Scholar
  102. 102.
    Fujiwara Y, Tatsumi M, Sasaki MS. Crosslink repair in human cells with its possible defects in Fanconi’s anemia cells. J Mol Biol 1977; 113:635–649.Google Scholar
  103. 103.
    Fujiwara Y. Defective repair of mitomycin C crosslinks in Fanconi’s anemia and loss in confluent normal human and xeroderma pigmentosum cells. Biochim Biophys Acts 1982; 699:217–225.Google Scholar
  104. 104.
    Fujiwara Y, Kano Y, Yamamoto Y. DNA interstrand cross-linking, repair and SCE mechanism in human cells in special reference to Fanconi anemia. In: Tice R, Hollaender A, eds. Sister Chromatid Exchanges. New York, Plenum Publishing Corp, 1984:787–800.Google Scholar
  105. 105.
    Laquerbe A, Moustacchi E, Fuscoe JC et al. The molecular mechanism underlying formation of deletions in Fanconi anemia cells may involve a site-specific recombination. Proc Natl Acad Sci USA 1995; 92:831–835.Google Scholar
  106. 106.
    Strathdee CA, Duncan AMV, Buchwald M. Evidence for at least four Fanconi’s anemia genes including FACC on chromosome 9. Nat Genet 1992; 1:196–198.Google Scholar
  107. 107.
    Strathdee CA, Gavish H, Shannon WR et al. Cloning of cDNAs for Fanconi’s anemia by functional complementation. Nature 1992; 356:763–767.Google Scholar
  108. 108.
    Yamashita T, Barber DL, Zhu Y et al. The Fanconi anemia polypeptide FACC is localized to the cytoplasm. Proc Natl Acad Sci USA 1994; 91:6712–6716.Google Scholar
  109. 109.
    Youssoufian H. Localization of Fanconi anemia C protein to the cytoplasm of mammalian cells. Proc Natl Acad Sci USA 1994; 91:7975–7979.Google Scholar
  110. 110.
    Digweed M, Sperling K. Molecular analysis of Fanconi anaemia. BioEssay 1996; 18:579–585.Google Scholar
  111. 111.
    Bloom D. Congenital telangiectatic erythema resembling lupus erythematosis in dwarfs. Am J Dis Child 1954; 88:754–758.Google Scholar
  112. 112.
    German J, Bloom D, Passarge E et al. Bloom’s syndrome. VI. the disorder in Israel, and an estimate of the gene frequency in the Ashkenazim. Am J Hum Genet 1977; 29:553–562.Google Scholar
  113. 113.
    Kuhn EM, Therman E. Cytogenetics of Bloom’s syndrome. Cancer Genet Cytogenet 1986; 22:1–18.Google Scholar
  114. 114.
    Krepinsky AB, Heddle JA, German J. Sensitivity of Bloom’s syndrome lymphocytes to ethyl methanesulfonate. Hum Genet 1979; 50:151–156.Google Scholar
  115. 115.
    Heddle JA, Krepinsky AB, Marshall RR. Cellular sensitivity to mutagens and carcinogens in the chromosome-breakage and other cancer-prone syndromes. In: German J, ed. Chromosome Mutation and Neoplasia. New York: Alan R. Liss, 1983:203–234.Google Scholar
  116. 116.
    Kurihara T, Inoue M, Tatsumi K. Hyper-sensitivity of Bloom’s syndrome fibro-blasts to N-ethyl-N-nitrosourea. Mutat Res 1987; 184:147–151.Google Scholar
  117. 117.
    Langlois RG, Bigbee WL, Jensen RH et al. Evidence for increased in vivo mutation and somatic recombination in Bloom’s syndrome. Proc Natl Acad Sci USA 1989; 86:670–674.Google Scholar
  118. 118.
    Lonn U, Lonn S, Nylen U et al. An abnormal profile of DNA replication intermediates in Bloom’s syndrome. Cancer Res 1990; 50:3141–3145.Google Scholar
  119. 119.
    Chan JY, Becker FF, German J et al. Altered DNA ligase I activity in Bloom’s syndrome cells. Nature 1987; 325:357–359.Google Scholar
  120. 120.
    Willis AE, Lindahl T. DNA ligase I deficiency in Bloom’s syndrome. Nature 1987; 325:355–357.Google Scholar
  121. 121.
    Petrini JHJ, Huwiler KG, Weaver DT. A wild-type DNA ligase I gene is expressed in Bloom’s syndrome cells. Proc Natl Acad Sci USA 1991; 88:7615–7619.Google Scholar
  122. 122.
    Ellis NA, Groden J, Ye T-Z et al. The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell 1995; 83:655–666.Google Scholar
  123. 123.
    Barnes DE, Tomkinson AE, Lehmann AR et al. Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA damaging agents. Cell 1992; 69:495–503.Google Scholar
  124. 124.
    Prigent C, Satoh MS, Daly G et al. Aberrant DNA repair and DNA replication due to an inherited enzymatic defect in human DNA ligase I. Mol Cell Biol 1994; 14:310–317.Google Scholar
  125. 125.
    Modrich P. Mismatch repair, genetic stability, and cancer. Science 1994; 266:1959–1960.Google Scholar
  126. 126.
    Modrich P. Mechanisms and biological effects of mismatch repair. Annu Rev Genet 1991; 25:229–253.Google Scholar
  127. 127.
    Jiricny J. Colon cancer and DNA repair: have mismatches met their match? Trends Genet 1994; 10:164–168.Google Scholar
  128. 128.
    Su S-S, Modrich P. Escherichia coli mutS-encoded protein binds to mismatched DNA base pairs. Proc Natl Acad Sci USA 1986; 83:5057–5061.Google Scholar
  129. 129.
    Parker BO, Marinus MG. Repair of heteroduplexes containing small heterologous sequences in Escherichia coli. Proc Natl Acad Sci USA 1992; 89:1730–1734.Google Scholar
  130. 130.
    Grilley M, Welsh KM, Su S-S et al. Isolation and characterization of the Escherichia coli mutL gene product. J Biol Chem 1989; 264:1000–1004.Google Scholar
  131. 131.
    Au KG, Welsh K, Modrich P. Initiation of methyl-directed mismatch repair. J Biol Chem 1992; 267:12142–12148.Google Scholar
  132. 132.
    Grilley M, Griffith J, Modrich P. Bidirectional excision in methyl-directed mismatch repair. J Biol Chem 1993; 268:11830–11837.Google Scholar
  133. 133.
    Rayssiguier C, Thaler DS, Radman M. The barrier to recombination between Escherichia coli and Salmonella typhimurium is disrupted in mismatch-repair mutants. Nature 1989; 342:396–401.Google Scholar
  134. 134.
    Lynch HT, Smyrk TC, Watson P et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 1993; 104:1535–1549.Google Scholar
  135. 135.
    Fishel R, Lescoe MK, Rao MRS et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993; 75:1027–1038.Google Scholar
  136. 136.
    Leach FS, Nicolaides NC, Papadopoulos N et al. Mutation of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993; 75:1215–1225.Google Scholar
  137. 137.
    Papadopoulos N, Nicolaides NC, Wei YF et al. Mutation of a mutL homolog in hereditary colon cancer. Science 1994; 263:1625–1629.Google Scholar
  138. 138.
    Parsons R, Li GM, Longley MJ et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell 1993; 75:1227–1236.Google Scholar
  139. 139.
    Bhattacharyya NP, Skandalis A, Ganesh A et al. Mutator phenotype in human colorectal carcinoma cell lines. Proc Natl Acad Sci USA 1994; 91:6319–6323.Google Scholar
  140. 140.
    Peinado MA, Malkhosyan S, Velazquez A et al. Isolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction. Proc Natl Acad Sci USA 1992; 89:10065–10069.Google Scholar
  141. 141.
    Thibodeau SN, Gren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993; 260:816–819.Google Scholar
  142. 142.
    Ionov Y, Peinado MA, Malkhosyan S et al. Ubiquitous somatic mutations in simple repeated sequences revel a new mechanism for colonie carcinogenesis. Nature 1993; 363:558–560.Google Scholar
  143. 143.
    Lindblom A, Tannergard P, Werelius B et al. Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nature Genet 1993; 5:279–282.Google Scholar
  144. 144.
    Kunkel TA. Nucleotide repeats. Slippery DNA and diseases. Nature 1993; 365:207–208.Google Scholar
  145. 145.
    Bronner CE, Baker PT, Morrison G et al. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994; 368:258–261.Google Scholar
  146. 146.
    Nicolaides VC, Papadopoulos N, Liu B et al. Mutations of two MMS homologues in hereditary nonpolyposis colon cancer. Nature 1994; 371:75–80.Google Scholar
  147. 147.
    Murray AW. Creative blocks: cell-cycle checkpoints and feedback controls. Nature 1992; 359:599–604.Google Scholar
  148. 148.
    Hartwell LH, Kastan MB. Cell cycle control and cancer. Science 1994; 266:1821–1828.Google Scholar
  149. 149.
    Hunter T. Braking the cycle. Cell 1993; 75:839–841.Google Scholar
  150. 150.
    Hartwell LH. Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 1992; 71:543–546.Google Scholar
  151. 151.
    Kuerbitz SJ, Plunkett BS, Walsh WV et al. Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 1992; 89:7491–7495.Google Scholar
  152. 152.
    Kastan MB, Onykwere O, Sidransky D et al. Participation of p53 protein in the cellular responses to DNA damage. Cancer Res 1991; 51:6304–6311.Google Scholar
  153. 153.
    Kastan MB, Zhan Q, El-Deiry WS et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 1992; 71:587–597.Google Scholar
  154. 154.
    Harper JW, Adami GR, Wei N et al. The p21 Cdk-interacting protein Cipl is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993; 75:805–816.Google Scholar
  155. 155.
    Dulic V, Kaufmann WK, Wilson SJ et al. p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest. Cell 1994; 76:1013–1023.Google Scholar
  156. 156.
    El-Deiry WS, Harper JW, O’Connor PM et al. WAF1/CIP1 is induced in p53-mediated G1 arrest and apoptosis. Cancer Res 1994; 54:1169–1174.Google Scholar
  157. 157.
    Waga S, Hannon GJ, Beach D et al. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 1994; 369:574–578.Google Scholar
  158. 158.
    Zhan Q, Lord KA, Alamo I et al. The gadd and MyD genes define a novel set of mammalian genes encoding acidic proteins that synergistically suppress cell growth. Mol Cell Biol 1994; 14:2361–2371.Google Scholar
  159. 159.
    El-Deiry WS, Tokino T, Velculescu VE et al. WAFl, a potential mediator of p53 tumor suppression. Cell 1993; 75:817–825.Google Scholar
  160. 160.
    Gronostajski RM, Goldberg AJ, Pardee AB. Energy requirement for degradation of tumor-associated protein p53. Mol Cell Biol 1984; 4:442–448.Google Scholar
  161. 161.
    Maltzman W, Czyzyk L. UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol Cell Biol 1984; 4:1689–1694.Google Scholar
  162. 162.
    Nelson WG, Kastan MB. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol Cell Biol 1994; 14:1815–1823.Google Scholar
  163. 163.
    Zambetti GP, Levine AJ. A comparison of the biological activities of wild-type and mutant p53. FASEB J 1993; 7:855–865.Google Scholar
  164. 164.
    Fields S, Jang SK. Presence of a potent transcription activating sequence in the p53 protein. Science 1990; 249:1046–1049.Google Scholar
  165. 165.
    Bargonetti J, Manfredi JJ, Chen X et al. A proteolytic fragment from the central region of p53 has marked sequence-specific DNA-binding activity when generated from wild-type but not from oncogenic mutant p53 protein. Genes Dev 1993; 7:2565–2574.Google Scholar
  166. 166.
    Halazonetis TD, Kandil AN. Conformational shifts propagate from the oligomerization domain of p53 to its tetrameric DNA binding domain and restore DNA binding to selected p53 mutants. EMBO J 1993; 12:5057–5064.Google Scholar
  167. 167.
    Pavletich NP, Chambers KA, Pabo CO. The DNA-binding domain of p53 contains the four conserved regions and the major mutation hot spot. Genes Dev 1993; 7:2556–2564.Google Scholar
  168. 168.
    Wang Y, Reed M, Wang P et al. p53 domains: identification and characterization of two autonomous DNA-binding regions. Genes Dev 1993; 7:2575–2586.Google Scholar
  169. 169.
    Stürzbecher HW, Brain R, Addison C et al. A C-terminal alpha helix plus basic motif is the major structural determinant of p53 tetramerization. Oncogene 1992; 7:1513–1523.Google Scholar
  170. 170.
    Wang P, Reed M, Wang Y et al. p53 domains: structure, oligomerization, and transformation. Mol Cell Biol 1994; 14:5182–5191.Google Scholar
  171. 171.
    Reed M, Woelker B, Wang P et al. The C-terminal domain of p53 recognizes DNA damaged by ionizing radiation. Proc Natl Acad Sci USA 1995; 92:9455–9459.Google Scholar
  172. 172.
    Wu L, Bayle JH, Elenbaas B et al. Alternatively spliced forms in the carboxy-terminal domain of the p53 protein regulate its ability to promote annealing of complementary single strands of nucleic acids. Mol Cell Biol 1995; 15:497–504.Google Scholar
  173. 173.
    Foord OS, Bhattacharya P, Reich Z et al. A DNA binding domain is contained in the C-terminus of wild type p53 protein. Nucleic Acids Res 1991; 19:5191–5198.Google Scholar
  174. 174.
    Huang L-C, Clarkin KC, Wahl GM. Sensitivity and selectivity of the DNA damage sensor responsible for activating p53-dependent G1 arrest. Proc Natl Acad Sci USA 1996; 93:4827–4832.Google Scholar
  175. 175.
    Bakalkin G, Yakovleva T, Seiivanova G et al. p53 binds single-stranded DNA ends and catalyzes DNA renaturation and strand transfer. Proc Natl Acad Sci USA 1994; 91:413–417.Google Scholar
  176. 176.
    Bakalkin G, Selivanova G, Yakovleva T et al. p53 binds single-stranded DNA ends through the C-terminal domain and internal DNA segments via the middle domain. Nucleic Acids Res 1995; 23:362–369.Google Scholar
  177. 177.
    Lee S, Elenbaas B, Levine A et al. p53 and its 14 kDa C-terminal domain recognize primary DNA damage in the form of insertion/deletion mismatches. Cell 1995; 81:1013–1020.Google Scholar
  178. 178.
    Knippshild U, Milne D, Campbell L et al. p53 N-terminus-targeted protein kinase activity is stimulated in response to wild type p53 and DNA damage. Oncogene 1996; 13:1387–1393.Google Scholar
  179. 179.
    Mummenbrauer T, Janus F, Müller B et al. p53 exhibits 3––5–exonuclease activity. Cell 1996; 85:1089–1099.Google Scholar
  180. 180.
    Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68:820–823.Google Scholar
  181. 181.
    Stanbridge EJ. The reemergence of tumor suppression. Cancer Cells 1989; 1:31–33.Google Scholar
  182. 182.
    Vogelstein B. A deadly inheritance. Nature 1990; 348:681–682.Google Scholar
  183. 183.
    Hollstein M, Sidransky D, Vogelstein B et al. p53 mutations in human cancers. Science 1991; 253:49–53.Google Scholar
  184. 184.
    Toguchida J, Yamaguchi T, Dayton SH et al. Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med 1992; 326:1301–1308.Google Scholar
  185. 185.
    Mercer WE, Shields MT, Amin M et al. Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc Natl Acad Sci USA 1990; 87:6166–6170.Google Scholar
  186. 186.
    Baker SJ, Markowitz S, Fearon ER et al. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 1990; 249:912–915.Google Scholar
  187. 187.
    Michalovitz D, Halevy O, Oren M. Conditional inhibition of transformation and of cell proliferation by a temperaturesensitive mutant of p53. Cell 1990; 62:671–680.Google Scholar
  188. 188.
    Eliyahu D, Michalovitz D, Eliyahu S et al. Wild-type p53 can inhibit oncogenemediated focus formation. Proc Natl Acad Sci USA 1989; 86:8763–8767Google Scholar
  189. 189.
    Chen P-L, Chen Y, Brookstein R et al. Genetic mechanisms of tumor suppression by the human p53 gene. Science 1990; 250:1576–1580.Google Scholar
  190. 190.
    Bischoff FZ, Yim SO, Pathak S et al. Spontaneous abnormalities in normal fibroblasts from patients with Li-Fraumeni cancer syndrome: aneuploidy and immortalization. Cancer Res 1990; 50:7979–7984.Google Scholar
  191. 191.
    Livingstone LR, White A, Sprouse J et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 1992; 70:923–935.Google Scholar
  192. 192.
    Yin Y, Tainsky MA, Bischoff FZ et al. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 1992; 70:937–948.Google Scholar
  193. 193.
    Stenger J, Mayr G, Mann K et al. Formation of stable p53 homotetramers and multiple of tetramers. Mol Carcinog 1992; 5:102–106.Google Scholar
  194. 194.
    Kraiss S, Quaiser A, Oren M et al. Oligomerization of oncoprotein p53. J Virol 1988; 62:4737–4744.Google Scholar
  195. 195.
    Herskowitz I. Functional inactivation of genes by dominant negative mutations. Nature 1987; 329:219–222.Google Scholar
  196. 196.
    Eliyahu D, Goldfinger N, Pinhasi-Kimhi O et al. Meth A fibrosarcoma cells express two transforming mutant p53 species. Oncogene 1988; 3:313–321.Google Scholar
  197. 197.
    Levine AJ, Momand J, Finlay CA. The p53 tumour suppressor gene. Nature 1991; 351:453–456.Google Scholar
  198. 198.
    Lane DP, Benchimol S. p53: oncogene or antioncogene? Genes Dev 1990; 4:1–8.Google Scholar
  199. 199.
    Baker SJ, Fearon ER, Nigro JM et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 1989; 244:217–221.Google Scholar
  200. 200.
    Oka K, Ishikawa J, Bruner JM et al. Detection of loss of heterozygosity in the p53 gene in renal cell carcinoma and bladder cancer using the polymerase chain reaction. Mol Carcinog 1991; 4:10–13.Google Scholar
  201. 201.
    Nigro JM, Baker SJ, Preisinger AC et al. Mutations in the p53 gene occur in diverse human tumour types. Nature 1989; 342:705–708.Google Scholar
  202. 202.
    Mulligan LM, Matlashewski GJ, Scrable HJ et al. Mechanisms of p53 loss in human sarcomas. Proc Natl Acad Sci USA 1990; 87:5863–5867.Google Scholar
  203. 203.
    Li FP, Fraumeni JF. Soft-tissue sarcomas, breast cancer, and other neoplasms: a familial syndrome? Ann Intern Med 1969; 71:747–753.Google Scholar
  204. 204.
    Li FP, Fraumeni JF, Mulvihill JJ et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988; 48:5358–5362.Google Scholar
  205. 205.
    Malkin D, Li, FP, Strong LC et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250:1233–1238.Google Scholar
  206. 206.
    Srivastava S, Zou Z, Pirollo K et al. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 1990; 348:747–749.Google Scholar
  207. 207.
    Boder E., Sedgwick RP. Ataxiatelangiectasia. A familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics 1957; 21:526–554.Google Scholar
  208. 208.
    Swift M. Genetic aspects of ataxiatelangiectasia. Immunodef Rev 1990; 2:67–81.Google Scholar
  209. 209.
    Morrell D, Cromartie E, Swift M. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst 1986; 77:89–92.Google Scholar
  210. 210.
    Swift M, Morrell D, Cromartie E et al. The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 1986; 39: 573–583.Google Scholar
  211. 211.
    Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol 1994; 66:S177–S182.Google Scholar
  212. 212.
    Taylor AMR, Harnden DG, Arlett CF et al. Ataxia-telangiectasia: a human mutation with abnormal radiation sensitivity. Nature 1975; 258:427–429.Google Scholar
  213. 213.
    Paterson MC, Smith PJ. Ataxia telangiectasia: an inherited human disorder involving hypersensitivity to ionizing radiation and related DNA-damaging chemicals. Annu Rev Genet 1979; 13:291–398.Google Scholar
  214. 214.
    Lambert C, Schultz R, Smith M et al. Functional complementation of ataxiatelangiectasia group D (AT-D) cells by microcell-mediated chromosome transfer and mapping of the AT-D locus to the region 11q22-23. Proc Natl Acad Sci USA 1991; 88:5907–5911.Google Scholar
  215. 215.
    Meyn MS. High spontaneous intrachromosomal recombination rates in ataxia-telangiectasia. Science 1993; 260:1327–1330.Google Scholar
  216. 216.
    Luo CM, Tang W, Mekeel KL et al. High frequency and error-prone DNA recombination in ataxia telangiectasia cell lines. J Biol Chem 1996; 271:4497–4503.Google Scholar
  217. 217.
    Arlett CF, Priestly A. An assessment of the radiosensitivity of ataxiatelangiectasia. In: Gatti RA, Smith M, eds. Ataxia-Telangiectasia: Genetics, Neuropathology, and Immunology of a Degenerative Disease of Childhood. New York: Alan R. Liss, 1985:1–63.Google Scholar
  218. 218.
    Houldsworth J, Lavin MF. Effect of ionizing radiation on DNA synthesis in ataxia telangiectasia cells. Nucleic Acids Res 1980; 8:3709–3720.Google Scholar
  219. 219.
    Painter RB, Young BR. Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc Natl Acad Sci USA 1980; 77:7315–7317.Google Scholar
  220. 220.
    Zampetti-Bosseler F, Scott D. Cell death, chromosome damage and mitotic delay in normal human, ataxia telangiectasia and retinoblastoma fibroblasts after X-irradiation. Int J Radiat Biol 1981; 39:547–558.Google Scholar
  221. 221.
    Rudolph NS, Latt SA. Flow cytometric analysis of X-ray sensitivity in ataxia telangiectasia. Mutat Res 1989; 211:31–41.Google Scholar
  222. 222.
    Sedgwick RP, Boder E. Ataxiatelangiectasia. Handbook of Clinical Neurology 1991; 16:347–423.Google Scholar
  223. 223.
    Amromin GD, Boder E, Teplitz R. Ataxiatelangiectasia with a 32 year survival. A clinicopathological report. J Neuropathol Exp Neurol 1979; 38:621–643.Google Scholar
  224. 224.
    Agamanolis DP, Greenstein JI. Ataxiatelangiectasia: report of a case with Lewy bodies and vascular abnormalities within cerebral tissue. J Neuropathol Exp Neurol 1979; 39:475–489.Google Scholar
  225. 225.
    Meyn MS. Ataxia-telangiectasia and cellular responses to DNA damage. Cancer Res 1995; 55:5991–6001.Google Scholar
  226. 226.
    Meyn MS, Strasfeld L, Allen C. Testing the role of p53 in genetic instability and apoptosis in ataxia telangiectasia. Int J Radiat Biol 1994; 66:141–149.Google Scholar
  227. 227.
    Savitsky K, Bar-Shira A, Gilad S et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995; 268:1749–1753.Google Scholar
  228. 228.
    Stack JH, Emr SD. Vps34p required for yeast vacuolar protein sorting is a multiple specificity kinase that exhibits both protein kinase and phosphatidylinositolspecific PI 3-kinase activities. J Biol Chem 1994; 269:31552–31562.Google Scholar
  229. 229.
    Al-Khodairy F, Carr AM. DNA repair mutants defining G2 checkpoint pathways in Schizosaccharomyces pombe. EMBO J 1992; 11:1343–1350.Google Scholar
  230. 230.
    Rowley R, Subramani S, Young PG. Checkpoint controls in Schizosaccharomyces pombe: rad1. EMBO J 1992; 11:1335–1342.Google Scholar
  231. 231.
    Kato R, Ogawa H. An essential gene, ESR1, is required for mitotic cell growth, DNA repair and meiotic recombination in Saccharomyces cerevisiae. Nucleic Acids Res 1994; 22:3104–3112.Google Scholar
  232. 232.
    Hari KL, Santerre A, Sekelsky JJ et al. The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell 1995; 82:815–821.Google Scholar
  233. 233.
    Weinert TA, Kiser GL, Hartwell LH. Mitotic checkpoint genes in budding yeast and the dependence of mitosis on DNA replication and repair. Genes Dev 1994; 8:652–665.Google Scholar
  234. 234.
    Paulovich AG, Hartwell LH. A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage. Cell 1995; 82:841–847.Google Scholar
  235. 235.
    Lu X, Lane DP. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes. Cell 1993; 75:765–778.Google Scholar
  236. 236.
    Khanna KK, Lavin MF. Ionizing radiation and UV induction of p53 protein by different pathways in ataxia-telangiectasia cells. Oncogene 1993; 8:3307–3312.Google Scholar
  237. 237.
    Canman CE, Wolff AC, Chen CY et al. The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia. Cancer Res 1994; 54:5054–5058.Google Scholar
  238. 238.
    Artuso M, Esteve A, Bresil H et al. The role of the ataxia telangiectasia gene in the p53, WAF1/CIP1 (p21)-and GADD45-mediated response to DNA damage produced by ionising radiation. Oncogene 1995; 11:1427–1435.Google Scholar
  239. 239.
    Downes C, Wilkins AS. Cell cycle checkpoints, DNA repair and DNA replication strategies. BioEssays 1994; 16:75–79.Google Scholar
  240. 240.
    Blattner C, Knebel A, Radler-Pohl C et al. DNA damaging agents and growth factors induce changes in the program of expressed gene products through common routes. Environ Mol Mutagen 1994; 24:3–10.Google Scholar
  241. 241.
    Armitage P, Doll R. The age distribution of cancer and a multistage theory of carcinogenesis. Br J Cancer 1954; 8:1–12.Google Scholar
  242. 242.
    Vogelstein B, Kinzler K. The multistep nature of cancer. Trends Biochem Sci 1993; 9:138–141.Google Scholar
  243. 243.
    Loeb LA. Microsatellite instability: marker of a mutator phenotype in cancer. Cancer Res 1994; 54:5059–5063.Google Scholar
  244. 244.
    Tlsty TD. Normal diploid human and rodent cells lack a detectable frequency of gene amplification. Proc Natl Acad Sci USA 1990; 87:3132–3136Google Scholar
  245. 245.
    Wright JA, Smith HS, Watt FM et al. DNA amplification is rare in normal human cells. Proc Natl Acad Sci USA 1990; 87:791–1795.Google Scholar
  246. 246.
    Cavazzana-Calvo M, Le Deist F, De Saint Basile G et al. Increased radiosensitivity of granulocyte macrophage colony-forming units and skin fibroblasts in human autosomal recessive severe combined immunodeficiency. J Clin Invest 1993; 91:1214–1218.Google Scholar
  247. 247.
    Bentley DJ, Selfridge J, Millar JK et al. DNA ligase I is required for fetal liver erythropoiesis but is not essential for mammalian cell viability. Nature Genetics 1996; 13:489–491.Google Scholar
  248. 248.
    Umar A, Buermeyer AB, Simon JA et al. Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Cell 1996; 87:65–73.Google Scholar
  249. 249.
    Park MS, Ludwig DL, Stigger E et al. Physical interaction between human RAD52 and RPA is required for homologous recombination in mammalian cells. J Biol Chem 1996; 271:18996–19000.Google Scholar
  250. 250.
    Longhese MP, Neecke H, Paciotti V. The 70 kDa subunit of replication protein A is required for the G1/S and intra-S damage checkpoints in budding yeast. Nucleic Acids Res 1996; 24:3533–3537.Google Scholar
  251. 251.
    Yang YY, Johnson AL, Johnston LH et al. A mutation in a Saccharomyces cerevisiae gene (RAD3) required for nucleotide excision repair and transcription increases the efficiency of mismatch correction. Genetics 1996; 144:459–466.Google Scholar
  252. 252.
    Leadon SA, Cooper PK. Preferential repair of ionizing radiation-induced damage in the transcribed strand of an active human gene is defective in Cockayne syndrome. Proc Natl Acad Sci USA 1993; 90:10499–10503.Google Scholar
  253. 253.
    Kaufmann WK, Paules RS. DNA damage and cell cycle checkpoints. FASEB J 1996; 10:238–247.Google Scholar

Copyright information

© R.G. Landes Company 1997

Authors and Affiliations

  • Hanspeter Naegeli
    • 1
  1. 1.Institute of Pharmacology and ToxicologyUniversity of Zürich-TierspitalZürichSwitzerland

Personalised recommendations