Role of Nonhomologous End-Joining and Recombinational DNA Repair in Resistance to Nitrogen Mustard and DNA Crosslinking Agents

  • Lawrence C. Panasci
  • Zhi-Yuan Xu
  • Raquel Aloyz
Part of the Cancer Drug Discovery and Development book series (CDD&D)


The nitrogen mustards are an important group of alkylating agents with activity against several human tumors (1–4). Many nitrogen mustard analogs are transported by carrier-mediated systems into cells and alkylate DNA, RNA, and proteins (5–7). Alkylation of DNA and, more specifically, the formation of DNA interstrand crosslinks have been considered to be responsible for their cytotoxicity (8–10). Resistance to the nitrogen mustards in murine and human tumor cells has been reported to be secondary to (1) alterations in the transport of these agents (11), (2) alterations in the kinetics of the DNA crosslinks formed by these agents (9,10,12), (3) cytoplasmic metabolism of the chloroethyl alkylating moiety to the inactive hydroxyethyl derivative (13) via glutathione (GSH)/ glutathione-S-transferase (GST) (14–16), (4) overexpression of metallothionein, which confers resistance to cis-platinum and cross-resistance to melphalan (17), (5) changes in resistance to apoptosis (18), and (6) altered DNA repair activity (se e Fig. 1) (19). There have been previous reports of alterations in the kinetics of DNA interstrand crosslink formation and removal associated with resistance to the nitrogen mustards (9,10,12), although others have found no differences in the ability of sensitive or resistant cells to remove nitrogen mustard-induced crosslinks (20, 21). This review will concentrate on the involvement of DNA repair in nitrogen mustard drug resistance and cross-resistance to cisplatin. We will discuss results obtained in clinical samples and human cancer cell lines.


Chronic Lymphocytic Leukemia Nucleotide Excision Repair Chronic Lymphocytic Leukemia Patient Nitrogen Mustard Homologous Recombinational Repair 
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.
    Ochoa M Jr. Alkylating agents in clinical chemotherapy. Ann NYAcad Sci 1969;163:921–930.CrossRefGoogle Scholar
  2. 2.
    Bergsagel DE, Griffith KM, Haut A, et al. The treatment of plasma cell myeloma. Adv Cancer Res 1967;10:311–359.PubMedCrossRefGoogle Scholar
  3. 3.
    Fisher B, Carbone P, Economou SG, et al. L-Phenylalanine mustard (L-Pam) in the manage-ment of primary breast cancer. N Engl J Med 1975;292:117–122.PubMedCrossRefGoogle Scholar
  4. 4.
    Young RC, Chabner BA, Hubbard SP, et al. Advanced ovarian adenocarcinoma. N Engl JMed 1978;299:1261–1266.CrossRefGoogle Scholar
  5. 5.
    Goldenberg GJ, Land HB, Cormack DV. Mechanism of cyclophosphamide transport by L5178Y lymphoblasts in vitro. Cancer Res 1974;34:3274–3282.Google Scholar
  6. 6.
    Tew KD, Taylor DM. Studies with cyclophosphamide labelled with phosphorus-32:nucleic acid alkylation and its effect on DNA synthesis in rat tumor and normal tissues. J Natl Cancer Inst 1977;58:1413–1419.PubMedGoogle Scholar
  7. 7.
    Hoes I, Lemiere F, Van Dongen W, et al. Analysis of melphalan adducts of 2’-deoxynucleotides in calf thymus DNA hydrolysates by capillary high-pressure liquid chromatography-electrospray tandem mass spectroscopy. J Chromatogr B Biochem Sci Appl 1999;736:43–59.Google Scholar
  8. 8.
    Ross WE, Ewig RA, Kohn KW. Differences between melphalan and nitrogen mustard in the formation and removal of DNA crosslinks. Cancer Res 1978;38:1502–1506.PubMedGoogle Scholar
  9. 9.
    Zwelling L, Michaels S, Schwartz H, et al. DNA crosslinking as an indicator of sensitivity and resistance of L1210 leukemia cells to cis-diaminedichloroplatinum (II) and L>-phenylalanine mustard. Cancer Res 1981;41:640–649.PubMedGoogle Scholar
  10. 10.
    Parsons PG, Carter FB, Morrison L, et al. Mechanism of melphalan resistance developed in vitro in human melanoma cells. CancerRes 1981;41:1525–1534.PubMedGoogle Scholar
  11. 11.
    11. Moscow JA, Swanson CA, Cowan KH. Decreased melphalan accumulation in a human breast cancer cell line selected for resistance to melphalan. Br J Cancer 1993;68:32–37.CrossRefGoogle Scholar
  12. 12.
    Parsons PC. Dependence on treatment time of melphalan resistance and DNA crosslinking in human melanoma cell lines. Cancer Res 1984;44:2773–2778.PubMedGoogle Scholar
  13. 13.
    Suzukake K, Vistica BP, Vistica DT. Dechlorination of L-phenylalanine mustard by sensitive and resistance tumor cells and its relationship to intracellular glutathione content. Biochem Pharmacol 1983;32:165–167.PubMedCrossRefGoogle Scholar
  14. 14.
    Green JA, Vistica DT, Young RC, et al.Potentiation of melphalan cytotoxicity in human ovarian cancer cell lines by glutathione depletion. Cancer Res 1984;44:5427–5431.PubMedGoogle Scholar
  15. 15.
    Kramer RA, Greene K, Ahmad S, et al. Chemosensitization of L-phenylalanine mustard by the thiol-modulating agent buthionine sulfoximine. Cancer Res 1987;47:1593–1597.PubMedGoogle Scholar
  16. 16.
    Morgan AS, Ciaccio PJ, Tew KD, et al. Isozyme specific glutathione S-transferase inhibitors potentiate drug sensitivity in cultured human tumor cell lines. Cancer CherrmotherPharmacol 1996;37:363–370.CrossRefGoogle Scholar
  17. 17.
    Kelley SL, Basu A, Teicher BA, et al.Overexpression of metallothionein confers resistance to anticancer drugs. Science 1998;241:1813–1815.CrossRefGoogle Scholar
  18. 18.
    Reed JC. Bcl-2 family proteins: regulators of apoptosis and chemoresistance in hematologic malignancies. Semis Hernatol 1997;34:9–19.Google Scholar
  19. 19.
    Tan KB, Mattern MR, Boyce RA, et al. Elevated topoisomerase II activity and altered chromatin in nitrogen mustard-resistant human cells. NCI Monogr 1987;4:95–98.PubMedGoogle Scholar
  20. 20.
    Dean SW, Johnson AB, Tew KD. A comparative analysis of drug-induced DNA effects in a nitrogen mustard resistant cell line expressing sensitivity in nitrosoureas. Biochem Pharmacol 1986;35:1171–1176.PubMedCrossRefGoogle Scholar
  21. 21.
    Robson CN, Lewis AD, Wolf CR, et al. Reduced levels of drug-induced DNA cross linking in nitrogen mustard-resistant Chinese hamster ovary cells expressing elevated glutathione-S-transferase activity. Cancer Res 1987;47:6022–6027.PubMedGoogle Scholar
  22. 22.
    Bank BB, Kanganis D, Liebes LF, et al. Chlorambucil pharmacokinetics and DNA binding in chronic lymphocytic leukemia lymphocytes. Cancer Res 1989;49:554–559.PubMedGoogle Scholar
  23. 23.
    Lawley PD, Brookes PJ. Interstrand crosslinking of DNA by difunctional alkylating agents. J Mol Biol 1967;25:143–160.PubMedCrossRefGoogle Scholar
  24. 24.
    Ojwang JO, Grueneberg DA, Loechler EL. Synthesis of a duplex oligonucleotide containing a nitrogen mustard interstrand DNA-DNA crosslink. Cancer Res 1989;49:6529–6537.PubMedGoogle Scholar
  25. 25.
    de Jong S, Zijlstra JG, Timmer-Bosscha H, et al. Detection of DNA crosslinks in tumor cells with the ethidium bromide fluorescence assay. Int J Cancer 1986;37:557–561.PubMedCrossRefGoogle Scholar
  26. 26.
    Kohn KW. DNA filter elution: a window on DNA damage in mammalian cells. BioEssays 1996;18:505–513.PubMedCrossRefGoogle Scholar
  27. 27.
    Kohn KW. Principles and Practice of DNA filter elution. Pharmacol Ther 1991;49:55–77.PubMedCrossRefGoogle Scholar
  28. 28.
    O’Connor PM, Kohn KW. Comparative pharmacokinetics of DNA lesion formation and removal following treatment of L1210 cells with nitrogen mustards. Cancer Common 1990;2:387–394.Google Scholar
  29. 29.
    Merk O, Speit G. Detection of crosslinks with the comet assay in relationship to genotoxicity and cytotoxicity. Environ Mol Mutagen 1999;33:167–172.PubMedCrossRefGoogle Scholar
  30. 30.
    Merk O, Reiser K, Speit G. Analysis of chromate-induced DNA-protein crosslinks with the comet assay. Mutat Res 2000;471:71–80.PubMedCrossRefGoogle Scholar
  31. 31.
    Foon KA, Rai KR, Gale RP. Chronic lymphocytic leukemia: new insights into biology and therapy. Ann Int Med 1990;113:525–539.PubMedGoogle Scholar
  32. 32.
    Bramson J, McQuillan A, Aubin R, et al.Nitrogen mustard drug resistant B-cell chronic lymphocytic leukemia as an in vivo model for crosslinking agent resistance. Mutat Res 1995;336:269–278.PubMedCrossRefGoogle Scholar
  33. 33.
    Hanson JA, Bentley DP, Bean EA, et al. In vitro chemosensitivity testing in chronic lymphocytic leukaemia patients. Leuk Res 1991;15:565–569.PubMedCrossRefGoogle Scholar
  34. 34.
    Silber R, Degar B, Costin D, et al. Chemosensitivity of lymphocytes from patients with B-cell chronic lymphocytic leukemia to chlorambucil, fladarabine, and camptothecin analogs. Blood 1994;84:3440–3446.PubMedGoogle Scholar
  35. 35.
    Panasci L, Henderson D, Skalski V, et al. Transport, metabolism, and DNA interaction of melphalan in lymphocytes from patients with chronic lymphocytic leukemia. Cancer Res 1988;48:1972–1976.PubMedGoogle Scholar
  36. 36.
    Torres-Garcia SJ, Cousineau L, Caplan S, et al.Correlation of resistance to nitrogen mustards in chronic lymphocytic leukemia with enhanced removal of melphalan-induced DNA crosslinks. Biochem Pharmacol 1989;38:3122–3123.PubMedCrossRefGoogle Scholar
  37. 37.
    DeNeve W, Valeriote F, Edelstein M, et al. In vivo DNA crosslinking by cyclophosphamide: comparison of human lymphatic leukemia cells with mouse L1210 leukemia and normal bone marrow cells. Cancer Res 1989;49:3452–3456.PubMedGoogle Scholar
  38. 38.
    Johnston JB, Israels LG, Goldenberg GJ, et al. Glutathione S-transferase activity, sulfhydryl group and glutathione levels and DNA crosslinking activity with chlorambucil in chronic lymphocytic leukemia. J Nall Cancer Inst 1990;82:776–779.CrossRefGoogle Scholar
  39. 39.
    Batist G, Torres-Garcia S, Demuys JM, et al.Enhanced DNA crosslink removal: the apparent mechanism of resistance in a clinically relevant melphalan-resistant human breast cancer cell line. Mol Pharmacol 1989;36:224–230.PubMedGoogle Scholar
  40. 40.
    Bedford P, Fox BW. Repair of DNA interstrand crosslinks after busulphan. A possible mode of resistance. Cancer Chemother Pharmacol 1982;8:3–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Hill BT, Shellard SA, Hosking LK, et al. Enhanced DNA repair and tolerance of DNA damage associated with resistance to cis-diammine-dichloroplatinum (II) after in vitro exposure of a human teratoma cell line to fractionated X-irradiation. Int J Radiat Oncol Biol Phvs 1990;19:756–83.Google Scholar
  42. 42.
    Johnson SW, Swiggard PA, Handel LM, et al. Relationship between platinum-DNA adduct formation and removal and cisplatin cytotoxicity in cisplatin-sensitive and -resistant human ovarian cancer cells. Cancer Res 1994;54:5911–5916.PubMedGoogle Scholar
  43. 43.
    Ali-Osman F, Rairkar A, Young P. Formation and repair of 1,3-bis-(2-chloroethyl)-1-nitrosourea and cisplatin induced total genomic DNA interstrand crosslinks in human glioma cells. Cancer Biochem Biophys 1995;14:231–241.Google Scholar
  44. 44.
    Dong Q, Bullock N, Ali-Osman F, et al.Repair analysis of 4-hydroperoxycyclophosphamide-induced DNA interstrand crosslinking in the c-myc gene in 4-hydroperoxy-cyclophosphamide-sensitive and -resistant medulloblastoma cell lines. Cancer Chemother Pharmacol 1996;37:242–246.PubMedCrossRefGoogle Scholar
  45. 45.
    Rawlings CJ, Roberts JJ. Walker rat carcinoma cells are exceptionally sensitive to cisdiamminedichloroplatinum(II) (cisplatin) and other difunctional agents but not defective in the removal of platinum-DNA adducts. Mutat Res 1986;166:157–168.PubMedCrossRefGoogle Scholar
  46. 46.
    Petersen LN, Mamentaq EL, Stevnsner T, et al. Increased gene specific repair of cisplatin induced interstrand crosslinks in cisplatin resistant cell lines, and studies on carrier ligand specificity. Carcinogenesis 1996;17:2597–2602.PubMedCrossRefGoogle Scholar
  47. 47.
    Roy G, Horon JK, Roy R, et al. Acquired alkylating drug resistance of a human ovarian carcinoma cell line is unaffected by altered levels of pro- and anti-apoptotic proteins. Oncogene 2000;19:141–150.PubMedCrossRefGoogle Scholar
  48. 48.
    Mattes WB, Lee CS, Laval J, et al. Excision of DNA adducts of nitrogen mustards by bacterial and mammalian 3-methyladenine-DNA glycosylases. Carcinogenesis 1996;17:643–648.PubMedCrossRefGoogle Scholar
  49. 49.
    Geleziunas R, McQuillan A, Malapetsa A, et al. Increased DNA synthesis and repair-enzyme expression in lymphocytes from patients with chronic lymphocytic leukemia resistant to nitrogen mustards. J Natl Cancer Inst 1991;83:557–564.PubMedCrossRefGoogle Scholar
  50. 50.
    Bramson J, O’Connor T, Panasci LC. Effect of alkyl-N-purine DNA glycosylase overexpression on cellular resistance to bifunctional alkylating agents. Biochem Pharmacol 1995;50:39–44.PubMedCrossRefGoogle Scholar
  51. 51.
    Allan JM, Engelward BP, Dreslin AJ, et al. Mammalian 3-methyladenine DNA glycosylase protects against the toxicity and clastogenicity of certain chemotherapeutic DNA crosslinking agents. Cancer Res 1998;58:3965–3973.PubMedGoogle Scholar
  52. 52.
    Hoy CA, Thompson LH, Mooney CL, et al. Defective DNA crosslink removal in Chinese hamster cell mutants hypersensitive to bifunctional alkylating agents. Cancer Res 1985;45:1737–1743.PubMedGoogle Scholar
  53. 53.
    Caldecott K, Jeggo P. Cross-sensitivity of gamma-ray-sensitive hamster mutants to crosslinking agents. Mutat Res 1991;255:111–121.PubMedCrossRefGoogle Scholar
  54. 54.
    Tanaka T, Yamagami T, Oka Y, et al. The scid mutation in mice causes defects in the repair system for both double strand DNA breaks and DNA crosslinks. Mutat Res 1993;288:277–280.PubMedCrossRefGoogle Scholar
  55. 55.
    Essers J, Hendriks RW, Swagemakers SMU, et al. Disruption of mouse RAD54 reduces ionizing radiation resistance and homologous recombination. Cell 1997;89:195–204.PubMedCrossRefGoogle Scholar
  56. 56.
    Liu N, Lamerdin JE, Tebbs RS, et al. Xrcc-2 and Xrcc-3, new human Rad51-family members, promote chromosome stability and protect against DNA crosslinks and other damages. Mol Cell 1998;1:783–793.PubMedCrossRefGoogle Scholar
  57. 57.
    Thompson LH. Evidence that mammalian cells possess homologous recombinational repair pathways. Mutat Res 1996;363:77–88.PubMedCrossRefGoogle Scholar
  58. 58.
    Thompson LH, Schild D. Homologous recombinational repair of DNA ensures mammalian chromosome stability. Mutat Res 2001;477:131–153.PubMedCrossRefGoogle Scholar
  59. 59.
    Anderson CW, Lees-Miller SP. The nuclear serine/threonine protein kinase DNA-dependent protein kinase. Crit Rev Eukarvot Gene Expr 1992;2:283–314.Google Scholar
  60. 60.
    Jeggo PA. DNA-dependent protein kinase at the cross-roads of biochemistry and genetics. Mutat Res 1997;384:1–14.PubMedCrossRefGoogle Scholar
  61. 61.
    Shinohara A, Ogawa T. Rad51/RecA protein families and the associated proteins in eukaryotes. Mutat Res 1999;435:13–21.PubMedCrossRefGoogle Scholar
  62. 62.
    Bramson J, McQuillan A, Panasci LC. DNA repair enzyme expression in chronic lymphocytic leukemia vis-à-vis nitrogen mustard drug resistance. Cancer Lett 1995;90:139–148.PubMedCrossRefGoogle Scholar
  63. 63.
    Barret J-M, Calsou P, Laurent G, Salles B. DNA repair activity in protein extracts of fresh human malignant lymphoid cells. Mol Pharmacol 1996;49:766–771.PubMedGoogle Scholar
  64. 64.
    Bentley P, Salter R, Blackmore J, et al. The sensitivity of chronic lymphocytic leukaemia lymphocytes to irradiation in vitro. Leuk Res 1995;19:985–988.CrossRefGoogle Scholar
  65. 65.
    Lees-Miller SP, Chen YR, Anderson CW. Human cells contain a DNA-activated proteinkinase that phosphorylates simian virus 40T antigen, mouse p53 and the human Ku autoantigen. Mol Cell Biol 1990;10:6472–6481.Google Scholar
  66. 66.
    Muller C, Salles B. Regulation of DNA dependent protein kinase activity in leukemic cells. Oncogene 1997;15:2343–2348.PubMedCrossRefGoogle Scholar
  67. 67.
    Muller C, Christodoulopoulos G, Salles B, et al. DNA-dependent protein kinase activity correlates with clinical and in vitro sensitivity of chronic lymphocytic leukemia lymphocytes to nitrogen mustards. Blood 1998;92:2213–2219.PubMedGoogle Scholar
  68. 68.
    Christodoulopoulos G, Muller C, Salles B, et al. Potentiation of chlorambucil cytotoxicity in B-cell chronic lymphocytic leukemia by inhibition of DNA-dependent protein kinase activity using Wortmannin. Cancer Res 1998;58:1789–1792.PubMedGoogle Scholar
  69. 69.
    Wang ZM, Chen ZP, Xu ZY, et al. Xrcc-3 protein expression and induction of Rad51 foci correlate with melphalan resistance in human tumor cell lines. J Nall Cancer Inst 2001;93:1473–1478.CrossRefGoogle Scholar
  70. 70.
    Moll U, Lau R, Sypes MA, et al. DNA-dependent protein kinase, the DNA-activated protein kinase is differentially expressed in normal and malignant human tissues. Oncogene 1999;18:3114–3126.PubMedCrossRefGoogle Scholar
  71. 71.
    Jackson SP. DNA-dependent protein kinase. Innt J Biochern Cell Biol 1997;29:935–938.CrossRefGoogle Scholar
  72. 72.
    Song Q, Lees-Miller SP, Kumar S, et al. DNA-dependent protein kinase catalytic subunit: a target for an ICE-like protease in apoptosis. EMBO 1996;15:3238–3246.Google Scholar
  73. 73.
    Starostik P, Manshouri T, O’Brien S, et al. Deficiency of the ATM protein expression defines an aggressive subgroup of B-cell chronic lymphocytic leukemia. Cancer Res 1998;58:4552–4557.PubMedGoogle Scholar
  74. 74.
    Bullrich F, Rasio D, Kitada S, et al. ATM mutations in B-cell chronic lymphocytic leukemia. Cancer Res 1999;59:24–27.PubMedGoogle Scholar
  75. 75.
    Stankovic T, Weber P, Stewart G, et al. Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet 1999;353:26–29.PubMedCrossRefGoogle Scholar
  76. 76.
    Schaffner C, Stilgenbauer S, Rappold GA, et al. Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia. Blood 1999;94:748–753.PubMedGoogle Scholar
  77. 77.
    Bessho T, Mu D, Sancar A. Initiation of DNA interstrand crosslink repair in humans: the nucleotide excision repair system makes dual incisions 5’ to the crosslinked base and removes a 22 to 28-nucleotide-long damage-free strand. Mol Cell Biol 1997;17:6822–6830.PubMedGoogle Scholar
  78. 78.
    De Silva IU, McHugh PJ, Clingen PH, et al. Defining the roles of nucleotide excision repair and recombination in the repair of DNA interstrand crosslinks in mammalian cells. Mol Cell Biol 2000;20:7980–7990.PubMedCrossRefGoogle Scholar
  79. 79.
    Hays SL, Firmenich AA, Massey P, et al. Studies of the interaction between Rad52 protein and the yeast single-stranded DNA binding protein RPA. Mol Cell Biol 1998;18:4400–4406.PubMedGoogle Scholar
  80. 80.
    Bishop DK, Ear U, Bhattacharyya A, et al. Xrcc-3 is required for assembly of Rad51 complexes in vivo. J Biol Chem 1998;273:21482–21488.Google Scholar
  81. 81.
    Tan TL, Essers J, Citterio E, et al.Mouse Rad54 affects DNA conformation and DNA-damaged induced Rad51 foci formation. Curr Biol 1999;9:325–328.PubMedCrossRefGoogle Scholar
  82. 82.
    Christodoulopoulos G, Malapetsa A, Schipper H, et al. Chlormabucil induction of HsRad51 in B-cell chronic lymphocytic leukemia. Clin Cancer Res 1999;5:2178–2184.PubMedGoogle Scholar
  83. 83.
    Bello VE, Aloyz RS, Christodoulopoulos G, et al. Homologous recombinational repair visà-vis chlorambucil resistance in chronic lymphocytic leukemia. Biochem Pharmacol 2002;63:1585–1588.PubMedCrossRefGoogle Scholar
  84. 84.
    Slupianek A, Schmutte C, Tombine G, et al. BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance. Mol Cell 2001;8:795–806.PubMedCrossRefGoogle Scholar
  85. 85.
    Slupianek A, Hoser G, Majsterek I, et al. Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis. Mol Cell Biol 2002;22:4189–4201.PubMedCrossRefGoogle Scholar
  86. 86.
    Vispe S, Cazaux C, Lesca C, et al. Overexpression of Rad51 protein stimulates homologous recombination and increases resistance of mammalian cells to ionizing radiation. Nucleic Acids Res. 1998;26:2859–2864.PubMedCrossRefGoogle Scholar
  87. 87.
    Xu R, Aloyz R, Panasci LC. Xrcc-3 overexpression results in melphalan/cisplatin drug resistance. Proc Am Assoc Cancer Res 2002;43:424.Google Scholar
  88. 88.
    Xu Z, Chen Z-P, Malapetsa A, et al. DNA repair protein levels vis-à-vis anticancer drug resistance in the human tumor cell lines of the National Cancer Institute drug screening program. Anticancer Drugs 2002;13:511–519.PubMedCrossRefGoogle Scholar
  89. 89.
    Egly JM. The 14th Datta Lecture. T11F1IH: from transcription to clinic. FEBS Lett 2001;498:124–128.CrossRefGoogle Scholar
  90. 90.
    Damia G, Imperatori L, Stefanini M, et al. Sensitivity of CHO mutant cell lines with specific defects in nucleotide excision repair to different anti-cancer agents. Intl J Cancer 1996:66:779–783.CrossRefGoogle Scholar
  91. 91.
    Aloyz R, Xu Z-Y, Bello V, et al. Regulation of cisplatin resistance and homologous recom-bination repair by the TFIIH subunit XPD. Cancer Res. 2002;62:5457–5462.PubMedGoogle Scholar
  92. 92.
    Van Dyck E, Stasiak AZ, Stasiak A, et al. Binding of double-strand breaks in DNA by human Rad52 protein. Nature 1999;398:728–731.PubMedCrossRefGoogle Scholar
  93. 93.
    Walworth NC. Cell-cycle checkpoint kinases: checking in on the cell cycle. Curr Opin Cell Biol 2000:12:697–704.PubMedCrossRefGoogle Scholar
  94. 94.
    Falck J, Mailand N, Syljuasen RG, et al. The ATM-Chk2-Cdc25A checkpoint pathway guards acainst radioresistant DNA synthesis. Nature 2001;410:842–847.PubMedCrossRefGoogle Scholar
  95. 95.
    Abraham RT. Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 2001;15:2177–2196.PubMedCrossRefGoogle Scholar
  96. 96.
    Cliby WA, Roberts CJ, Cimprich KA, et al. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J 1998;17:159–169.PubMedCrossRefGoogle Scholar
  97. 97.
    Falck J, Petrini JH, Williams BR, et al. The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nature Genet 2002;30:290–294.PubMedCrossRefGoogle Scholar
  98. 98.
    Lim DS, Kim ST, Xu B, Maser RS, et al. ATM phorphorylates p95/nbs 1 in an S-phase checkpoint pathway. Nature 2000;404:613–617.PubMedCrossRefGoogle Scholar
  99. 99.
    Guo N, Faller DV, Vaziri C. Carcinogen-induced S-phase arrest is Chkl mediated and caffeine sensitive. Cell Growth Differ 2002;13:77–86.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Lawrence C. Panasci
  • Zhi-Yuan Xu
  • Raquel Aloyz

There are no affiliations available

Personalised recommendations