• Martin Digweed
  • Karl Sperling
Part of the Molekulare Medizin book series (MOLMED)


Unabhängig voneinander haben Schröder (1964) und German (1965) festgestellt, dass eine erhöhte Rate somatischer Chromosomenveränderungen ein charakteristisches Merkmal zweier autosomal-rezessiver Krankheiten darstellt, der Fanconi-Anämie (FA) bzw. des Bloom-Syndroms (BS). Heute ist dieses „Symptom“namensgebend für eine Gruppe von Erkrankungen, zu denen als wichtigste noch die Ataxia teleangiectatica (AT) und das Nijmegenbreakage-Syndrom (NBS) zählen. Hinzu kommen das Werner- und das Rothmund-Thomson-Syndrom, die so genannte AT-ähnliche Erkrankung (ATLD; Mre11-Defizienz). Als Begleitsymptom wurde eine erhöhte spontane bzw. induzierte Chromosomeninstabilität auch für eine Reihe weiterer Krankheiten beschrieben, wie z.B. die Ligase-I- und -IV-Defizienz sowie die Dyskeratosis congenita. Die Zahl dieser Erkrankungen wird weiter zunehmen, wie bereits aus theoretischen Überlegungen (s. unten) zu folgern ist.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ababou M, Dutertre S, Lecluse Y et al. (2000) ATM-dependent phosphorylation and accumulation of endogenous BLM protein in response to ionizing radiation. Oncogene 19:5955–5963PubMedGoogle Scholar
  2. Alter BP (1996) Fanconi’s anemia and malignancies. Am J Hematol 53:99–110PubMedGoogle Scholar
  3. Andegeko, Y, Moyal L, Mittelman L et al. (2001) Nuclear retention of ATM sites of DNA double strand breaks. J Biol Chem 276:38224–38230PubMedGoogle Scholar
  4. Antoccia A, Stumm M, Saar K et al. (1999) Impaired p53-mediated DNA damage response, cell-cycle disturbance and chromosome aberrations in Nijmegen breakage syndrome lymphoblastoid cell lines. Int J Radiat Biol 75:583–591PubMedGoogle Scholar
  5. Athma P, Rappaport R, Swift M (1996) Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 92:130–134PubMedGoogle Scholar
  6. Auerbach AD, Verlander PC (1997) Disorders of DNA replication and repair. Curr Opin Pediatr 9:600–616PubMedGoogle Scholar
  7. Bahr A, De Graeve F, Kedinger C, Chatton B (1998) Point mutations causing Bloom’s syndrome abolish ATPase and DNA helicase activities of the BLM protein. Oncogene 17:2565–2571PubMedGoogle Scholar
  8. Barnes DE, Tomkinson AE, Lehmann AR, Webster DB, Lindahl T (1992) Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents. Cell 69:495–503PubMedGoogle Scholar
  9. Baxevanis AD, Landsman D (1995) The HMG-I box protein family: classification and functional relationships. Nucleic Acids Res 23:1604–1613PubMedGoogle Scholar
  10. Becker-Catania SG, Gatti RA (2001) Ataxia-telangiectasia. Adv Exp Med Biol 495:191–198PubMedGoogle Scholar
  11. Bekiesinska-Figatowska M, Chrzanowska KH, Sikorska J et al. (2000) Cranial MRI in the Nijmegen breakage syndrome. Neuroradiology 42:43–47PubMedGoogle Scholar
  12. Bender MA, Griggs HG, Walker PL (1973) Mechanisms of chromosomal aberration production: I. Aberration production by ultraviolet light. Mutat Res 20:387–402PubMedGoogle Scholar
  13. Bischof O, Kim SH, Irving J et al. (2001) Regulation and localization of the Bloom syndrome protein in response to DNA damage. J Cell Biol 153:367–380PubMedGoogle Scholar
  14. Bressan DA, Baxter BK, Petrini JH (1999) The Mre11-Rad50-Xrs2 protein complex facilitates homologous recombination-based double-strand break repair in Saccharomyces cerevisiae. Mol Cell Biol 19:7681–7687PubMedGoogle Scholar
  15. Brown KD, Barlow C, Wynshaw-Boris A (1999) Multiple ATM-dependent pathways: an explanation for pleiotropy. Am J Hum Genet 64:46–50PubMedGoogle Scholar
  16. Busch DB, Zdzienicka MZ, Natarajan AT et al. (1996) A CHO mutant, UV40, that is sensitive to diverse mutagens and represents a new complementation group of mitomycin C sensitivity. Mutat Res 363:209–221PubMedGoogle Scholar
  17. Carney JP, Maser RS, Olivares H et al. (1998) The hMRE11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477–486PubMedGoogle Scholar
  18. Cerosaletti KM, Desai-Mehta A, Yeo TC et al. (2000) Retroviral expression of the NBS1 gene in cultured Nijmegen breakage syndrome cells restores normal radiation sensitivity and nuclear focus formation. Mutagenesis 15:281–286PubMedGoogle Scholar
  19. Chakraverty RK, Hickson ID (1999) Defending genome integrity during DNA replication: a proposed role for RecQ family helicases. Bioessays 21:286–294PubMedGoogle Scholar
  20. Chen J, Birkholtz GG, Lindblom P, Rubio C, Lindblom A (1998) The role of ataxia-telangiectasia heterozygotes in familial breast cancer. Cancer Res 58:1376–1379PubMedGoogle Scholar
  21. Chen HT, Bhandoola A, Difilippantonio MJ et al. (2000) Response to RAG-mediated VDJ cleavage by NBS1 and gamma-H2AX. Science 290:1962–1965PubMedGoogle Scholar
  22. Chrzanowska KH, Kleijer WJ, Krajewska-Walasek M et al. (1995) Eleven Polish patients with microcephaly, immunodeficiency, and chromosomal instability: the Nijmegen breakage syndrome. Am J Med Genet 57:462–471PubMedGoogle Scholar
  23. Collins A, Johnson RT (1987) DNA repair mutants in higher eukaryotes. J Cell Sci Suppl 6:61–82PubMedGoogle Scholar
  24. Cornforth MN (1998) Radiation-induced damage and the formation of chromosomal aberrations. In: Nickoloff JA, Hoekstra MF (eds) DNA damage and repair, vol 2, DNA repair in higher eukaryotes. Humana Press, Totowa, NJ, pp 559–585Google Scholar
  25. Costanzo V, Robertson K, Bibikova M et al. (2001) Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication. Mol Cell 8:137–147PubMedGoogle Scholar
  26. D’Amours D, Jackson SP (2002) The Mre11 complex: at the crossroads of DNA repair and checkpoint signalling. Nat Rev Mol Cell Biol 3:317–327PubMedGoogle Scholar
  27. Dawson JP (1955) Congenital pancytopenia associated with mutliple congenital anomalies (Fanconi type). Pediatrics 15:325–333PubMedGoogle Scholar
  28. Demuth I, Wlodarski M, Tipping AJ et al. (2000) Spectrum of mutations in the Fanconi anemia group G gene, FANCG/XRCC9. Eur J Hum Genet 8:861–868PubMedGoogle Scholar
  29. Desai-Mehta A, Cerosaletti KM, Concannon P (2001) Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization. Mol Cell Biol 21:2184–2191PubMedGoogle Scholar
  30. De Schouwer PJ, Dyer MJ, Brito-Babapulle VB et al. (2000) T-cell prolymphocytic leukaemia: antigen receptor gene rearrangement and a novel mode of MTCP1 B1 activation. Br J Haematol 110:831–838PubMedGoogle Scholar
  31. Digweed M, Sperling K (1989) Identification of a HeLa mRNA fraction which can correct the DNA-repair defect in Fanconi anaemia fibroblasts. Mutat Res 218:171–177PubMedGoogle Scholar
  32. Digweed M, Sperling K (1996) Molecular analysis of Fanconi anaemia. Bioessays 18:579–585PubMedGoogle Scholar
  33. Digweed M, Zakrzewski-Lüdcke S, Sperling K (1988) Fanconis anaemia: correlation of genetic complementation group with psoralen/UVA response. Hum Genet 78:51–54PubMedGoogle Scholar
  34. Digweed M, Reis A, Sperling K (1999) Nijmegen breakage syndrome: consequences of defective DNA double strand break repair. Bioessays 21:649–656PubMedGoogle Scholar
  35. Digweed M, Demuth I, Rothe S et al. (2002a) SV40 large T-antigen disturbs the formation of nuclear DNA-repair foci containing MRE11. Oncogene 21:4873–4878PubMedGoogle Scholar
  36. Digweed M, Rothe S, Demuth I et al. (2002b) Attenuation of the formation of DNA-repair foci containing RAD51 in Fanconi anaemia. Carcinogenesis 23:1121–1126PubMedGoogle Scholar
  37. Dokal I, Luzzatto L (1994) Dyskeratosis congenita is a chromosomal instability disorder. Leuk Lymphoma 15:1–7PubMedGoogle Scholar
  38. Dolganov GM, Maser RS, Novikov A et al. (1996) Human Rad50 is physically associated with human Mre11. Identification of a conserved multiprotein complex implicated in recombinational DNA repair. Mol Cell Biol 16:4832–4841PubMedGoogle Scholar
  39. Dong Z, Zhong Q, Chen PL (1999) The Nijmegen breakage syndrome protein is essential for Mre11 phosphorylation upon DNA damage. J Biol Chem 274:19513–19516PubMedGoogle Scholar
  40. Ellis NA, Groden J, Ye TZ et al. (1995a) The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell 83:655–666PubMedGoogle Scholar
  41. Ellis NA, Lennon DJ, Proytcheva M et al. (1995b) Somatic intragenic recombination within the mutated locus BLM can correct the high sister-chromatid exchange phenotype of Bloom syndrome cells. Am J Hum Genet 57:1019–1027PubMedGoogle Scholar
  42. Faivre L, Guardiola P, Lewis C et al. (2000) Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group. Blood 96:4064–4070PubMedGoogle Scholar
  43. Fanconi G (1927) Familiäre infantile perniziosaartige Anämie (perniziöses Blutbild und Konstitution). Jahrb Kinderheükd 117:257–280Google Scholar
  44. FitzGerald MG, Bean JM, Hegde SR et al. (1997) Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 15:307–310PubMedGoogle Scholar
  45. Flores-Rozas H, Kolodner RD (2000) Links between replication, recombination and genome instability in eukaryotes. Trends Biochem Sci 25:196–200PubMedGoogle Scholar
  46. Furuichi Y (2001) Premature aging and predisposition to cancers caused by mutations in RecQ family helicases. Ann NY Acad Sci 928:121–131PubMedGoogle Scholar
  47. Futaki M, Yamashita T, Yagasaki H et al. (2000) The IVS4+4 A to T mutation of the Fanconi anemia gene FANCC is not associated with a severe phenotype in Japanese patients. Blood 95:1493–1498PubMedGoogle Scholar
  48. Gangloff S, McDonald JP, Bendixen C, Arthur L, Rothstein R (1994) The yeast type I topoisomerase Top3 interacts with Sgsl, a DNA helicase homolog: a potential eukaryotic reverse gyrase. Mol Cell Biol 14:8391–8398PubMedGoogle Scholar
  49. Garcia-Higuera I, Taniguchi T, Ganesan S et al. (2001) Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell 7:249–262PubMedGoogle Scholar
  50. Gatei M, Young D, Cerosaletti KM et al. (2000) ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nat Genet 25:115–119PubMedGoogle Scholar
  51. Gatti RA (1998) Ataxia-telangiectasia. In: Vogelstein B, Kinzler KW (eds) The genetic basis of human cancer. McGraw-Hill, New York, pp 275–300Google Scholar
  52. Gatti RA (2001) The inherited basis of human radiosensitivity. Acta Oncol 40:702–711PubMedGoogle Scholar
  53. Gatti RA, Tward A, Concannon P (1999) Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Genet Metab 68:419–423PubMedGoogle Scholar
  54. German J (1997) Bloom’s syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet 93:100–106PubMedGoogle Scholar
  55. German J, Passarge E (1989) Bloom’s syndrome. XII. Report from the registry for 1987. Clin Genet 35:57–69PubMedGoogle Scholar
  56. German J, Archibald R, Bloom D (1965) Chromosomal breakage in a rare and probably genetically determined syndrome of man. Science 148:506–507PubMedGoogle Scholar
  57. German J, Roe AM, Leppert MF, Ellis NA (1994) Bloom syndrome: an analysis of consanguineous families assigns the locus mutated to chromosome band 15q26.1. Proc Natl Acad Sci USA 91:6669–6673PubMedGoogle Scholar
  58. Giampietro PF, Verlander PC, Davis JG, Auerbach AD (1997) Diagnosis of Fanconi anemia in patients without congenital malformations: an international Fanconi Anemia Registry Study. Am J Med Genet 68:58–61PubMedGoogle Scholar
  59. Gilad S, Khosravi R, Shkedy D et al. (1996) Predominance of null mutations in ataxia-telangiectasia. Hum Mol Genet 5:433–440PubMedGoogle Scholar
  60. Gilad S, Chessa L, Khosravi R et al. (1998) Genotype-phenotype relationships in ataxia-telangiectasia (AT) and AT variants. Am J Hum Genet 62:551–562PubMedGoogle Scholar
  61. Gillio AP, Verlander PC, Batish SD, Giampietro PF, Auerbach AD (1997) Phenotypic consequences of mutations in the Fanconi anemia FAC gene: an International Fanconi Anemia Registry study. Blood 90:105–110PubMedGoogle Scholar
  62. Glanz A, Fraser FC (1982) Spectrum of anomalies in Fanconi anaemia. J Med Genet 19:412–416PubMedGoogle Scholar
  63. Green AJ, Yates JR, Taylor AM et al. (1995) Severe microcephaly with normal intellectual development: the Nijmegen breakage syndrome. Arch Dis Child 73:431–434PubMedGoogle Scholar
  64. Gruenert DC, Cleaver JE (1985) Repair of psoralen-induced cross-links and monoadducts in normal and repair-deficient human fibroblasts. Cancer Res 45:5399–5404PubMedGoogle Scholar
  65. Haber JE (2000) Partners and pathways — repairing a double-strand break. Trends Genet 16:259–264PubMedGoogle Scholar
  66. Heim RA, Lench NJ, Swift M (1992) Heterozygous manifestations in four autosomal recessive human cancer-prone syndromes: ataxia telangiectasia, xeroderma pigmentosum, Fanconi anemia, and Bloom syndrome. Mutat Res 284:25–36PubMedGoogle Scholar
  67. Heiss NS, Knight SW, Vulliamy TJ et al. (1998) X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 19:32–38PubMedGoogle Scholar
  68. Hejna JA, Timmers CD, Reifsteck C et al. (2000) Localization of the Fanconi anemia complementation group D gene to a 200-kb region on chromosome 3p25.3. Am J Hum Genet 66:1540–1551PubMedGoogle Scholar
  69. Hopfner KP, Putnam CD, Tainer JA (2002) DNA doublestrand break repair from head to tail. Curr Opin Struct Biol 12:115–122PubMedGoogle Scholar
  70. Howlett NG, Taniguchi T, Olson S et al. (2002) Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297:606–609PubMedGoogle Scholar
  71. Ito A, Tauchi H, Kobayashi J et al. (1999) Expression of fulllength NBS1 protein restores normal radiation responses in cells from Nijmegen breakage syndrome patients. Biochem Biophys Res Commun 265:716–721PubMedGoogle Scholar
  72. Jackson SP (2002) Sensing and repairing DNA double-strand breaks. Carcinogenesis 23:687–696PubMedGoogle Scholar
  73. Jeggo PA, Carr AM, Lehmann AR (1998) Splitting the ATM: distinct repair und checkpoint defects in ataxia-telangiectasia. Trends Genet 14:312–316PubMedGoogle Scholar
  74. Joenje H, Patel KJ (2001) The emerging genetic and molecular basis of Fanconi anaemia. Nature 2:446–457Google Scholar
  75. Joenje H, Oostra AB, Wijker M et al. (1997) Evidence for at least eight Fanconi anemia genes. Am J Hum Genet 61:940–944PubMedGoogle Scholar
  76. Joenje H, Levitus M, Waisfisz Q et al. (2000) Complementation analysis in Fanconi anemia: assignment of the reference FA-H patient to group A. Am J Hum Genet 67:759–762PubMedGoogle Scholar
  77. Johnson RT, Gotoh E, Mullinger AM et al. (1999) Targeting double-strand breaks to replicating DNA identifies a subpathway of DSB repair that is defective in ataxia-telangiectasia cells. Biochem Biophys Res Commun 261:317–325PubMedGoogle Scholar
  78. Jongmans W, Vuillaume M, Chrzanowska K et al. (1997) Nijmegen breakage syndrome cells fail to induce the p53-mediated DNA damage response following exposure to ionizing radiation. Mol Cell Biol 17:5016–5022PubMedGoogle Scholar
  79. Karow JK, Chakraverty RK, Hickson ID (1997) The Bloom’s syndrome gene product is a 3′-5′ DNA helicase. J Biol Chem 272:30611–30614PubMedGoogle Scholar
  80. Karow JK, Constantinou A, Li JL, West SC, Hickson ID (2000a) The Bloom’s syndrome gene product promotes branch migration of holliday junctions. Proc Natl Acad Sci USA 97:6504–6508PubMedGoogle Scholar
  81. Karow JK, Wu L, Hickson ID (2000b) RecQ family helicases: roles in cancer and aging. Curr Opin Genet Dev 10:32–38PubMedGoogle Scholar
  82. Karran P (2000) DNA double strand break repair in mammalian cells. Curr Opin Genet Dev 10:144–150PubMedGoogle Scholar
  83. Kastan MB, Zhan Q, Deiry WS el et al. (1992) A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71:587–597PubMedGoogle Scholar
  84. Khanna KK, Jackson SP (2001) DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27:247–254PubMedGoogle Scholar
  85. Khanna KK, Gatti R, Concannon P et al. (1998) Cellular responses to DNA damage and human chromosome instability syndromes. In: Nickoloff JA, Hoekstra MF (eds) DNA damage and repair, vol 2, DNA repair in higher eukaryotes. Humana Press, Totowa, NJ, pp 395–442Google Scholar
  86. Khanna KK, Lavin MF, Jackson SP, Mulhern TD (2001) ATM, a central controller of cellular responses to DNA damage. Cell Death Differ 8:1052–1065PubMedGoogle Scholar
  87. Kitao S, Ohsugi I, Ichikawa K et al. (1998) Cloning of two new human helicase genes of the RecQ family: biological significance of multiple species in higher eukaryotes. Genomics 54:443–452PubMedGoogle Scholar
  88. Kitao S, Shimamoto A, Goto M et al. (1999) Mutations in RECQL4 cause a subset of cases of Rothmund-Thomson syndrome. Nat Genet 22:82–84PubMedGoogle Scholar
  89. Klocker H, Burtscher HJ, Auer B, Hirsch-Kaufmann M, Schweiger M (1985) Fibroblasts from patients with Fanconis anemia are not deficient in excision of thymine dimer. Eur J Cell Biol 37:240–242PubMedGoogle Scholar
  90. Kruyt FA, Hoshino T, Liu JM et al. (1998) Abnormal microsomal detoxification implicated in Fanconi anemia group C by interaction of the FAC protein with NADPH cytochrome P450 reductase. Blood 92:3050–3056PubMedGoogle Scholar
  91. Kuang Y, Garcia-Higuera I, Moran A et al. (2000) Carboxy terminal region of the Fanconi anemia protein, FANCG/XRCC9, is required for functional activity. Blood 96:1625–1632PubMedGoogle Scholar
  92. Kupfer GM, Naf D, Suliman A, Pulsipher M, D’Andrea AD (1997a) The Fanconi anaemia proteins, FAA and FAC, interact to form a nuclear complex. Nat Genet 17:487–490PubMedGoogle Scholar
  93. Kupfer GM, Yamashita T, Naf D et al. (1997b) The Fanconi anemia polypeptide, FAC, binds to the cyclin-dependent kinase, cdc2. Blood 90:1047–1054PubMedGoogle Scholar
  94. Kusano K, Berres ME, Engels WR (1999) Evolution of the RECQ familiy of helicases: a Drosophila homolog, Dmblm, is similar to the human bloom syndrome gene. Genetics 151:1027–1039PubMedGoogle Scholar
  95. Langlois RG, Bigbee WL, Jensen RH, German J (1989) Evidence for increased in vivo mutation and somatic recombination in Bloom’s syndrome. Proc Natl Acad Sci USA 86:670–674PubMedGoogle Scholar
  96. Larson GP, Zhang G, Ding S et al. (1997–98) An allelic variant at the ATM locus is implicated in breast cancer susceptibility. Genet Test 1:165–170PubMedGoogle Scholar
  97. Lavin MF (1999) ATM: the product of the gene mutated in ataxia-telangiectasia. Int J Biochem Cell Biol 31:735–740PubMedGoogle Scholar
  98. Lebel M, Leder P (1998) A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity. Proc Natl Acad Sci USA 95:13097–13102PubMedGoogle Scholar
  99. Levran O, Doggett NA, Auerbach AD (1998) Identification of Alu-mediated deletions in the Fanconi anemia gene FAA. Hum Mutat 12:145–152PubMedGoogle Scholar
  100. Lim DS, Kim ST, Xu B et al. (2000) ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 404:613–617PubMedGoogle Scholar
  101. Limoli CL, Giedzinski E, Morgan WF, Cleaver JE (2000) Polymerase eta deficiency in the xeroderma pigmentosum variant uncovers an overlap between the S phase checkpoint and double-strand break repair. Proc Natl Acad Sci USA 97:7939–7946PubMedGoogle Scholar
  102. Lindor NM, Furuichi Y, Kitao S et al. (2000) Rothmund-Thomson Syndrome due to RECQ4 helicase mutations: report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome. Am J Med Genet 90:223–228PubMedGoogle Scholar
  103. Loeb LA (1991) Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075–3079PubMedGoogle Scholar
  104. Lo Ten Foe JR, Rooimans MA, Bosnoyan-Collins L et al. (1996) Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA. Nat Genet 14:320–323Google Scholar
  105. Lombard DB, Guarente L (2000) Nijmegen breakage syndrome disease protein and MRE11 at PML nuclear bodies and meiotic telomeres. Cancer Res 60:2331–2334PubMedGoogle Scholar
  106. Luo G, Yao MS, Bender CF et al. (1999) Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation. Proc Natl Acad Sci USA 96:7376–7381PubMedGoogle Scholar
  107. Luo G, Santoro IM, McDaniel LD et al. (2000) Cancer predisposition caused by elevated mitotic recombination in Bloom mice. Nat Genet 26:424–429PubMedGoogle Scholar
  108. Marciniak RA, Johnson FB, Guarente L (2000) Dyskeratosis congenita, telomeres and human ageing. Trends Genet 16:193–195PubMedGoogle Scholar
  109. Maser RS, Monsen KJ, Nelms BE, Petrini JH (1997) hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks. Mol Cell Biol 17:6087–6096PubMedGoogle Scholar
  110. Maser RS, Zinkel R, Petrini JH (2001) An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. Nat Genet 27:417–421PubMedGoogle Scholar
  111. Matsuura S, Weemaes C, Smeets D et al. (1997) Genetic mapping using microcell-mediated chromosome transfer suggests a locus for Nijmegen breakage syndrome at chromosome 8q21–24. Am J Hum Genet 60:1487–1494PubMedGoogle Scholar
  112. Matsuura S, Tauchi H, Nakamura A et al. (1998) Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet 19:179–181PubMedGoogle Scholar
  113. McMahon LW, Walsh CE, Lambert MW (1999) Human alpha spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex. J Biol Chem 274:32904–32908PubMedGoogle Scholar
  114. Medhurst AL, Huber PA, Waisfisz Q, Winter JP de, Mathew CG (2001) Direct interactions of the five known Fanconi anemia proteins suggest a common functional pathway. Hum Mol Genet 10:423–429PubMedGoogle Scholar
  115. Meyn MS (1997) Chromosome instability syndromes: lessons for carcinogenesis. Curr Top Microbiol Immunol 221:71–148PubMedGoogle Scholar
  116. Meyn MS (1999) Ataxia-telangiectasia, cancer and the pathobiology of the ATM gene. Clin Genet 55:289–304PubMedGoogle Scholar
  117. Mirzoeva OK, Petrini JH (2001) DNA damage-dependent nuclear dynamics of the Mre11 complex. Mol Cell Biol 21:281–288PubMedGoogle Scholar
  118. Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402:551–555PubMedGoogle Scholar
  119. Moens PB, Freire R, Tarsounas M, Spyropoulos B, Jackson SP (2000) Expression and nuclear localization of BLM, a chromosome stability protein mutated in Bloom’s syndrome, suggest a role in recombination during meiotic prophase. J Cell Sci 113:663–672PubMedGoogle Scholar
  120. Morgan NV, Tipping AJ, Joenje H, Mathew CG (1999) High frequency of large intragenic deletions in the Fanconi anemia group A gene. Am J Hum Genet 65:1330–1341PubMedGoogle Scholar
  121. Moshous D, Callebaut I, Chasseval R de et al. (2001) Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105:177–186PubMedGoogle Scholar
  122. Myung K, Datta A, Chen C, Kolodner RD (2001) SGS1, the Saccharomyces cerevisiae homologue of BLM and WRN, suppresses genome instability and homeologous recombination. Nat Genet 27:113–116PubMedGoogle Scholar
  123. Näf D, Kupfer GM, Suliman A, Lambert K, D’Andrea AD (1998) Functional activity of the fanconi anemia protein FAA requires FAC binding and nuclear localization. Mol Cell Biol 18:5952–5960PubMedGoogle Scholar
  124. Natarajan AT, Obe G (1978) Molecular mechanisms involved in the production of chromosomal aberrations. I. Utilization of Neurospora endonuclease for the study of aberration production in G2 stage of the cell cycle. Mutat Res 69:137–149Google Scholar
  125. Natarajan AT, Obe G (1984) Molecular mechanisms involved in the production of chromosomal aberrations: III. Restriction endonucleases. Chromosoma 90:120–127PubMedGoogle Scholar
  126. Nelms BE, Maser RS, MacKay JF, Lagally MG, Petrini JH (1998) In situ visualization of DNA double-strand break repair in human fibroblasts. Science 280:590–592PubMedGoogle Scholar
  127. O’Driscoll M, Cerosaletti KM, Girard PM et al. (2001) DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 8:1175–1185PubMedGoogle Scholar
  128. Otsuki T, Kajigaya S, Ozawa K, Liu JM (1999) SNX5, a new member of the sorting nexin family, binds to the Fanconi anemia complementation group A protein. Biochem Biophys Res Commun 265:630–635PubMedGoogle Scholar
  129. Pandita TK, Hittelman WN (1992) The contribution of DNA and chromosome repair deficiencies to the radiosensitivity of ataxia-telangiectasia. Radiat Res 131:214–223PubMedGoogle Scholar
  130. Pang Q, Keeble W, Christianson TA, Faulkner GR, Bagby GC (2001) FANCC interacts with Hsp70 to protect hematopoietic cells from IFN-gamma/TNF-alpha-mediated cytotoxicity. EMBO J 20:4478–4489PubMedGoogle Scholar
  131. Pastink A, Eeken JCJ, Lohmann HM (2001) Genomic integrity and the repair of double-strand DNA breaks. Mutat Res 480–481:37–50PubMedGoogle Scholar
  132. Pauli TT, Geliert M (1998) The 3′ to 5′ exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. Mol Cell 1:969–979Google Scholar
  133. Petersen S, Casellas R, Reina-San-Martin B et al. (2001) AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching. Nature 414:660–665PubMedGoogle Scholar
  134. Petrini JH, Donovan JW, Dimare C, Weaver DT (1994) Normal V(D)J coding junction formation in DNA ligase I deficiency syndromes. J Immunol 152:176–183PubMedGoogle Scholar
  135. Petrini JH, Walsh ME, DiMare C et al. (1995) Isolation and characterization of the human MRE 11 homologue. Genomics 29:80–86PubMedGoogle Scholar
  136. Pitts SA, Kullar HS, Stankovic T et al. (2001) hMRE11: genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay. Hum Mol Genet 10:1155–1162PubMedGoogle Scholar
  137. Prigent C, Satoh MS, Daly G, Barnes DE, Lindahl T (1994) Aberrant DNA repair and DNA replication due to an inherited enzymatic defect in human DNA ligase I. Mol Cell Biol 14:310–317PubMedGoogle Scholar
  138. Pronk JC, Gibson RA, Savoia A et al. (1995) Localisation of the Fanconi anemia complementation group A gene to chromosome 16q24.3. Nat Genet 11:338–340PubMedGoogle Scholar
  139. Qiao F, Moss A, Kupfer G M (2001) Fanconi anemia proteins localize to chromatin and the nuclear matrix in a DNA damage and cell cycle-regulated manner. J Biol Chem 276:23391–23396PubMedGoogle Scholar
  140. Rattray AJ, Symington LS (1995) Multiple pathways for homologous recombination in Saccharomyces cerevisiae. Genetics 139:45–56PubMedGoogle Scholar
  141. Reveil SH (1959) The accurate estimate of chromatid breakage and its relevance to a new interpretation of chromatid aberrations induced by ionizing radiations. Proc R Soc Lond B Biol Sci 150:563–589Google Scholar
  142. Riballo E, Critchlow SE, Teo SH et al. (1999) Identification of a defect in DNA ligase IV in a radiosensitive leukaemia patient. Curr Biol 9:699–702PubMedGoogle Scholar
  143. Roa BB, Savino CV, Richards CS (1999) Ashkenazi Jewish population frequency of the Bloom syndrome gene 2281 delta 6ins7 mutation. Genet Test 3:219–221PubMedGoogle Scholar
  144. Rotman G, Shiloh Y (1998) ATM: from gene to function. Hum Mol Genet 7:1555–1563PubMedGoogle Scholar
  145. Saar K, Chrzanowska KH, Stumm M et al. (1997) The gene for the ataxia-telangiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21. Am J Hum Genet 60:605–610PubMedGoogle Scholar
  146. Saar K, Schindler D, Wegner R-D et al. (1998) Localisation of a Fanconi anemia gene to chromosome 9p. Eur J Hum Genet 6:501–508PubMedGoogle Scholar
  147. Sachs RK, Hlatky LR, Trask BJ (2000) Radiation-produced chromosome aberrations — colorful clues. Trends Genet 16:143–146PubMedGoogle Scholar
  148. Sandoval N, Platzer M, Rosenthal A et al. (1999) Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum Mol Genet 8:69–79PubMedGoogle Scholar
  149. Sanz MM, Proytcheva M, Ellis NA, Holloman WK, German J (2000) BLM, the Bloom’s syndrome protein, varies during the cell cycle in its amount, distribution, and co-localization with other nuclear proteins. Cytogenet Cell Genet 91:217–223PubMedGoogle Scholar
  150. Sasaki MS, Tonomura A (1973) A high susceptiblity of Fancorn’s anemia to chromosome breakage by DNA cross linking agents. Cancer Res 33:1829–1836PubMedGoogle Scholar
  151. Savitsky K, Bar-Shira A, Gilad S et al. (1995) A single ataxia-telangiectasia gene with a product similar to P1-3 kinase. Science 268:1749–1753PubMedGoogle Scholar
  152. Sax K (1940) An analysis of X-ray-induced chromosomal aberrations in Tradescantia. Genetics 25:42–68Google Scholar
  153. Schindler D, Hoehn H (1988) Fanconi anemia mutation causes cellular susceptibility to ambient oxygen. Am J Hum Genet 43:429–435PubMedGoogle Scholar
  154. Schroeder TM (1966) Cytogenetischer Befund und Ätiologie bei Fanconi-Anämie. Ein Fall von Fanconi-Anämie ohne Hexokinasedefekt. Humangenetik 3:76–81PubMedGoogle Scholar
  155. Schroeder TM, German J (1974) Bloom’s syndrome and Fancorn’s anemia: demonstration of two distinct patterns of chromosome disruption and rearrangement. Humangenetik 25:299–306PubMedGoogle Scholar
  156. Schroeder TM, Anschütz F, Knopp A (1964) Spontane Chromosomenaberrationen bei familiärer Panmyelopathie. Humangenetik 1:194–196PubMedGoogle Scholar
  157. Seemanova E (1990) An increased risk for malignant neoplasms in heterozygotes for a syndrome of microcephaly, normal intelligence, growth retardation, remarkable facies, immunodeficiency and chromosomal instability. Mutat Res 238:321–324PubMedGoogle Scholar
  158. Seemanova E, Passarge E, Beneskova D et al. (1985) Familial microcephaly with normal intelligence, immunodeficiency, and risk for lymphoreticular malignancies: a new autosomal recessive disorder. Am J Med Genet 20:639–648PubMedGoogle Scholar
  159. Seidemann K, Henze G, Beck JD et al. (2000) Non-Hodgkin’s lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS). Experience from the BFM trials. Ann Oncol 11:141–1451PubMedGoogle Scholar
  160. Seyschab H, Sun Y, Friedl R, Schindler D, Hoehn H (1993) G2 phase cell cycle disturbance as a manifestation of genetic cell damage. Hum Genet 92:61–68PubMedGoogle Scholar
  161. Shen J-C, Loeb LA (2000) The Werner syndrome gene — the molecular basis of RecQ helicase-deficiency diseases. Trends Genet 16:213–220PubMedGoogle Scholar
  162. Shiloh Y, Kastan MB (2001) ATM: genome stability, neuronal development, and cancer cross paths. Adv Cancer Res 83:209–254PubMedGoogle Scholar
  163. Sperling K, Neitzel H (2000) Chromosomopathien. In: Ganten D, Ruckpaul K (Hrsg) Monogen bedingte Erbkrankheiten 2. Handbuch der Molekularen Medizin, Bd 7. Springer, Berlin Heidelberg New York, S 43–77Google Scholar
  164. Stankovic T, Kidd AM, Sutcliffe A et al. (1998) ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet 62:334–345PubMedGoogle Scholar
  165. Stankovic T, Weber P, Stewart G et al. (1999) Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet 353:26–29PubMedGoogle Scholar
  166. Stewart GS, Maser RS, Stankovic T et al. (1999) The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99:577–587PubMedGoogle Scholar
  167. Stilgenbauer S, Schaffner C, Litterst A et al. (1997) Biallelic mutations in the ATM gene in T-prolymphocytic leukemia. Nat Med 3:1155–1159PubMedGoogle Scholar
  168. Strathdee CA, Duncan AM, Buchwald M (1992a) Evidence for at least four Fanconi anaemia genes including FACC on chromosome 9. Nat Genet 1:196–198PubMedGoogle Scholar
  169. Strathdee CA, Gavish H, Shannon WR, Buchwald M (1992b) Cloning of cDNAs for Fanconi’s anaemia by functional complementation. Nature 356:763–767PubMedGoogle Scholar
  170. Stumm M, Gatti RA, Reis A et al. (1995) The ataxia telangiectasia-variant genes 1 and 2 are distinct from the ataxia telangiectasia gene on chromosome 11q23.1. Am J Hum Genet 57:960–962PubMedGoogle Scholar
  171. Stumm M, Sperling K, Wegner RD (1997) Non-complementation of radiation induced chromosome aberrations in Ataxia-telangiectasia/Ataxia-telangiectasia-variant heterodikaryons. Am J Hum Genet 60:1246–1251PubMedGoogle Scholar
  172. Swift M (1971) Fanconi’s anaemia in the genetics of neoplasia. Nature 230:370–373PubMedGoogle Scholar
  173. Swift M, Caldwell RJ, Chase C (1980) Reassessment of cancer predisposition of Fanconi anemia heterozygotes. J Natl Cancer Inst 65:863–867PubMedGoogle Scholar
  174. Swift M, Reitnauer PJ, Morrell D, Chase CL (1987) Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 316:1289–1294PubMedGoogle Scholar
  175. Swift M, Kupper LL, Chase CL (1990) Effective testing of gene-disease associations. Am J Hum Genet 47:266–274PubMedGoogle Scholar
  176. Swift M, Morrell D, Massey RB, Chase CL (1991) Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med 325:1831–1836PubMedGoogle Scholar
  177. Taniguchi T, Garcia-Higuera I, Xu B et al. (2002) Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109:459–472PubMedGoogle Scholar
  178. Tauchi H (2000) Positional cloning and functional analysis of the gene responsible for Nijmegen breakage syndrome, NBS1. J Radiat Res 41:9–17PubMedGoogle Scholar
  179. Tauchi H, Kobayashi J, Morishima K et al. (2001) The forkhead-associated domain of NBS1 is essential for nuclear foci formation after irradiation but not essential for hRAD50-hMRE11-Nbs1 complex DNA repair activity. J Biol Chem 276:12–15PubMedGoogle Scholar
  180. The Fanconi anaemia/Breast cancer consortium (1996) Positional cloning of the Fanconi anaemia group A gene. Nat Genet 14:324–328Google Scholar
  181. The International Nijmegen Breakage Syndrome Study Group (2000) Nijmegen breakage syndrome. Arch Dis Child 82:400–406Google Scholar
  182. Timmers C, Taniguchi T, Hejna J et al. (2001) Positional cloning of a novel Fanconi anemia gene, FANCD2. Mol Cell 7:241–248PubMedGoogle Scholar
  183. Tipping AJ, Pearson T, Morgan NV et al. (2001) Molecular and genealogical evidence for a founder effect in Fanconi anemia families of the Afrikaner population of South Africa. Proc Natl Acad Sci USA 98:5734–5739PubMedGoogle Scholar
  184. Tomlinson I, Bodmer W (1999) Selection, the mutation rate and cancer: ensuring that the tail does not wag the dog. Nat Med 5:11–12PubMedGoogle Scholar
  185. Trujillo KM, Yuan SS, Lee EY, Sung P (1998) Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95. J Biol Chem 273:21447–21450PubMedGoogle Scholar
  186. Van de Kaa CA, Weemaes CM, Wesseling P et al. (1994) Postmortem findings in the Nijmegen breakage syndrome. Pediatr Pathol 14:787–796PubMedGoogle Scholar
  187. Van Gent DC, Hoeijmakers JHJ, Kanaar R (2001) Chromosomal stability and the DNA double-stranded break connection. Nature 2:196–206Google Scholar
  188. Van Gorp J, Doornewaard H, Verdonck LF et al. (1994) Posttransplant T-cell lymphoma. Report of three cases and a review of the literature. Cancer 73:3064–3072PubMedGoogle Scholar
  189. Varon R, Vissinga C, Platzer M et al. (1998) Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93:467–476PubMedGoogle Scholar
  190. Varon R, Seemanova E, K Chrzanowska et al. (2000) Clinical ascertainment of Nijmegen breakage syndrome (NBS) and prevalence of the major mutation, 657del5, in three Slav populations. Eur J Hum Genet 8:900–902PubMedGoogle Scholar
  191. Varon R, Reis A, Henze G et al. (2001) Mutations in the Nijmegen Breakage syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res 61:3570–3572PubMedGoogle Scholar
  192. Vorechovsky I, Luo L, Dyer MJ et al. (1997) Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nat Genet 17:96–99PubMedGoogle Scholar
  193. Waisfisz Q, Saar K, Morgan NV et al. (1999) The Fanconi anemia group E gene, FANCE, maps to chromosome 6p. Am J Hum Genet 64:1400–1405PubMedGoogle Scholar
  194. Walpita D, Plug AW, Neff NF, German J, Ashley T (1999) Bloom’s syndrome protein, BLM, colocalizes with replication protein A in meiotic prophase nuclei of mammalian spermatocytes. Proc Natl Acad Sci USA 96:5622–5627PubMedGoogle Scholar
  195. Wang Y, Cortez D, Yazdi P et al. (2000) BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14:927–939PubMedGoogle Scholar
  196. Warren ST, Schultz RA, Chang CC, Wade MH, Trosko JE (1981) Elevated spontaneous mutation rate in Bloom syndrome fibroblasts. Proc Natl Acad Sci USA 78:3133–3137PubMedGoogle Scholar
  197. Weemaes CM, Smeets DF, Burgt CJ van der (1994) Nijmegen Breakage syndrome. A progress report. Int J Radiat Biol 66:S185–188PubMedGoogle Scholar
  198. Wegner RD, Chrzanowska KH, Sperling K, Stumm M (1998) Ataxia-telangiectasia variants. In: Ochs HD, Smith CIE, Puck JM (eds) Primary immunodeficiency diseases: a molecular and genetic approach. Oxford University Press, Oxford, UK, pp 324–334Google Scholar
  199. Welcsh PL, Schubert EL, King MC (1998) Inherited breast cancer: an emerging picture. Clin Genet 54:447–458PubMedGoogle Scholar
  200. Whitney MA, Saito H, Jakobs PM et al. (1993) A common mutation in the FACC gene causes Fanconi anaemia in Ashkenazi Jews. Nat Genet 4:202–205PubMedGoogle Scholar
  201. Winter JP de, Waisfisz Q, Rooimans MA et al. (1998) The Fanconi anaemia group G gene FANCG is identical with XRCC9. Nat Genet 20:281–283PubMedGoogle Scholar
  202. Winter JP de, Leveille F, Van Berkel CG et al. (2000a) Isolation of a cDNA representing the Fanconi anemia complementation group E gene. Am J Hum Genet 67:1306–1308PubMedGoogle Scholar
  203. Winter JP de, Rooimans MA, Van der Weel L et al. (2000b) The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM. Nat Genet 24:15–16PubMedGoogle Scholar
  204. Winter JP de, Van der Weel L, Groot J de et al. (2000c) The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG. Hum Mol Genet 9:2665–2674PubMedGoogle Scholar
  205. Wu X, Ranganathan V, Weisman DS et al. (2000) ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 405:477–482PubMedGoogle Scholar
  206. Xie Y, de Winter JP, Waisfisz Q et al. (2000) Aberrant Fanconi anaemia protein profiles in acute myeloid leukaemia cells. Br J Haematol 111:1057–1064PubMedGoogle Scholar
  207. Yamaguchi-Iwai Y, Sonoda E, Sasaki MS et al. (1999) Mre11 is essential for the maintenance of chromosomal DNA in vertebrate cells. EMBO J 18:6619–6629PubMedGoogle Scholar
  208. Yu C-E, Oshima J, Fu Y-H et al. (1996) Positional cloning of the Werner’s syndrome gene. Science 272:258–262PubMedGoogle Scholar
  209. Zakrzewski S, Sperling K (1980) Genetic heterogeneity of Fanconi’s anaemia demonstrated by somatic cell-hybrids. Hum Genet 56:81–84PubMedGoogle Scholar
  210. Zdzienicka MZ (1996) Mammalian X ray sensitive mutants: a tool for the elucidation of the cellular response to ionizing radiation. Cancer Surv 28:281–291PubMedGoogle Scholar
  211. Zhao S, Weng YC, Yuan S-SF et al. (2000) Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature 405:473–477PubMedGoogle Scholar
  212. Zhou B-BS, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439PubMedGoogle Scholar
  213. Zhu J, Petersen S, Tessarollo L, Nussenzweig A (2001) Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr Biol 11:105–109PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • Martin Digweed
  • Karl Sperling

There are no affiliations available

Personalised recommendations