Bleomycins: Towards better therapeutics

Nature Reviews Cancer

Volumn 5, Issue 2, 2005, Pages 102-112

  Chen, Jingyang ^a   Stubbe, JoAnne ^a  

^a MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; ANTINEOPLASTIC AGENT; BLEOMYCIN; DOUBLE STRANDED DNA; GLYCOPEPTIDE; SINGLE STRANDED DNA; TRANSITION ELEMENT;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BIOSYNTHESIS; CYTOTOXICITY; DNA DAMAGE; DRUG EFFICACY; GERM CELL TUMOR; HEAD AND NECK CANCER; HUMAN; INTERSTITIAL PNEUMONIA; LUNG FIBROSIS; LUNG TOXICITY; LYMPHOMA; MUTAGENIC ACTIVITY; NONHUMAN; PNEUMONIA; PRIORITY JOURNAL; REVIEW; SQUAMOUS CELL CARCINOMA;

ANIMALS; ANTI-BACTERIAL AGENTS; BIOLOGICAL TRANSPORT; BLEOMYCIN; DNA; DNA DAMAGE; DNA REPAIR; DNA, SINGLE-STRANDED; FIBROSIS; HELA CELLS; HUMANS; LUNG; MODELS, BIOLOGICAL; MODELS, CHEMICAL; MODELS, GENETIC; MODELS, MOLECULAR; MUTAGENS; MUTATION; NEOPLASMS;

EID: 13444257678     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc1547     Document Type: Review

References (116)

1. Umezawa, H., Maeda, K., Takeuchi, T. & Okami, Y. New antibiotics, bleomycin A and B. J. Antibiot. (Tokyo) 19, 200-209 (1966).
2. Levi, J. A. et al. The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. Australasian Germ Cell Trial Group. J. Clin. Oncol. 11, 1300-1305 (1993).
3. Einhom, L. H. Curing metastatic testicular cancer. Proc. Natl Acad. Sci. USA 99, 4592-4595 (2002).
4. Sikic, B. I., Rozencweig, M. & Carter, S. K. Bleomycin Chemotherapy (Academic, Orlando, Florida, 1985).
5. Bayer, R. A., Gaynor, E. R. & Fisher, R. I. Bleomycin in non-Hodgkin's lymphoma. Semin. Oncol. 19, 46-52 (1992).
6. Boggs, S. S., Sartiano, G. P. & DeMezza, A. Minimal bone marrow damage in mice given bleomycin. Cancer Res. 34, 1938-1942 (1974).
7. Lehane, D. E., Hurd, E. & Lane, M. The effects of bleomycin on immunocompetence in man. Cancer Res. 35, 2724-2728 (1975).
8. Sleijfer, S. Bleomycin-induced pneumonitis. Chest 120, 617-624 (2001).
9. Burger, R. M., Peisach, J. & Horwitz, S. B. Activated bleomycin: a transient complex of drug, iron, and oxygen that degrades DNA. J. Biol. Chem. 256, 11636-11644 (1961).
10. Ekimoto, H., Takahashi, K., Matsuda, A., Takita, T. & Umezawa, H. Lipid peroxidation by bleomycin-iron complexes in vitro. J. Antibiot. (Tokyo) 38, 1077-1082 (1985).
11. Rana, T. M. & Meares, C. F. Transfer of oxygen from an artificial protease to peptide carbon during proteolysis. Proc Natl Acad. Sci. USA 88, 10578-10582 (1991).
12. Hecht, S. M. RNA degradation by bleomycin, a naturally occurring bioconjugate. Bioconjugate Chem. 5, 513-526 (1994).
13. Stubbe, J. & Kozarich, J. W. Mechanisms of bleomycin-induced DNA degradation. Chem. Rev. 87, 1107-1136 (1987).
14. Stubbe, J., Kozarich, J. W., Wu, W. & Vanderwall, D. E. Bleomycins: a structural model for specificity, binding, and double strand cleavage. Acc. Chem. Res. 29, 322-330 (1996).
15. Boger, D. L. & Cai, H. Bleomycin: Synthetic and mechanistic studies. Angew. Chem. Int. Ed. 38, 449-176 (1999). A comprehensive review on synthetic bleomycin analogues and their ability to cleave DNA. The results indicate that bleomycin is a finely tuned machine, the parts of which act synergistically to efficiently effect dsDNA cleavage.
16. Hecht, S. M. Bleomycin: new perspectives on the mechanism of action. J. Nat. Prod. 63, 158-168 (2000).
17. D'Andrea, A. D. & Haseltine, W. A. Sequence specific cleavage of DNA by the antitumor antibiotics neocarzinostatin and bleomycin. Proc. Natl Acad. Sci. USA 75, 3608-3612 (1978).
18. 2: evidence for intercalation using 2D NMR. J. Am. Chem. Soc. 116, 10843-10844 (1994).
19. Povirk, L. F., Hogan, M. & Dattagupta, N. Binding of bleomycin to DNA: Intercalation of the bithiazole Rings. Biochemistry 18, 96-101 (1979).
20. Abraham, A. T., Zhou, X. & Hecht, S. M. Metallobleomycin-mediated cleavage of DNA not involving a threading-intercalation mechanism. J. Am. Chem. Soc. 123, 5167-5175 (2001).
21. 2. J. Am. Chem. Soc. 120, 2239-2250 (1998).
22. Tounekti, O., Kenani, A., Foray, N., Ortowski, S. & Mir, L. M. The ratio of single- to double-strand DNA breaks and their absolute values determine cell death pathway. Br. J. Cancer. 84, 1272-1279 (2001). By controlling bleomycin's uptake using electroporation, the authors demonstrated that the extent of dsDNA cleavage is dependent on the Intracellular bleomycin concentration, the extent of which dictates cellular responses.
23. Hecht, S. M. Bleomycin combinatorial libraries: a strategy for identifying mechanism of action and improved analogues. Eur. J. Cancer 38, S13-S14 (2002).
24. Rishel, M. J. & Hecht, S. M. Analogues of bleomycin: Synthesis of conformationally rigid methylvalerates. Org. Lett. 3, 2867-2869 (2001).
25. Leitheiser, C. J. et al. Solid-phase synthesis of bleomycin group antibiotics: Construction of a 108-member deglycobleomycin library. J. Am. Chem. Soc. 125, 8218-8227 (2003).
26. Povirk, L. F., Wübker, W., Köhnleín, W. & Hutchinson, F. DNA Double-strand breaks and alkali-labile bonds produced by bleomycin. Nucleic Acids Res. 4, 3573-3580 (1977).
27. Absalon, M. J., Wu, W., Kozarich, J. W. & Stubbe, J. Sequence-specific double-strand cleavage of DNA by Fe bleomycin. 2. Mechanism and dynamics. Biochemistry 34, 2076-2086 (1995).
28. Vanderwall, D. E. et al. A model of the structure of HOO- Co•bleomycin bound to d(CCAGTACTGG): recognition at the d(GpT) site and implications for double-stranded DNA cleavage. Chem. Biol. 4, 373-387 (1997). The structure of bleomycin-Co(III)-OOH bound sequence specifically to an oligonucleotide duplex containing a hot spot for dsDNA cleavage. This structure leads to the current model for how a single molecule of bleomycin can effect dsDNA cleavage.
29. Kuo, M. T. & Hsu, T. C. Bleomycin causes release of nucleosomes from chromatin and chromosomes. Nature 271, 83-04 (1978).
30. Kuo, M. T. & Hsu, T. C. Biochemical and cytological studies of bleomycin actions on chromatin and chromosomes. Chromosoma (Berl.) 68, 229-240 (1978).
31. Smith, B. L., Bauer, G. B. & Povirk, L. F. DNA damage induced by bleomycin, neocarzinostatin, and melphalan in a precisely positioned nucleosome. J. Biol. Chem. 269, 30587-30594 (1994). Bleomycin's ability to cleave nucleosomes was examined. The results indicate that bleomycin binds DNA by intercalation.
32. Kunimoto, T., Hori, M. & Umezawa, H. Modes of action of phleomycin, bleomycin and formycin on HeLa S3 cells in synchronized culture. J. Antibiot. (Tokyo) 20, 277-281 (1967).
33. Tobey, R. A. A simple, rapid technique for determination of the effects of chemotherapeutic agents on mammalian cell-cycle traverse. Cancer Res. 32, 309-316 (1972).
34. Ohama, K. & Kadotani, T. Cytologic effects of bleomycin on cultured human leukocytes. Jap. J. Human Genet. 14, 293-297 (1970).
35. Vig, B. K. & Lewis, R. Genetic toxicology of bleomycin. Mutat. Res. 55, 121-145 (1978).
36. Suzuki, H., Nagai, K., Yamaki, H., Tanaka, N. & Umezawa, H. On the mechanism of action of bleomycin: scission of DNA strands in vitro and in vivo. J. Antibiot. (Tokyo) 22, 446-448 (1969).
37. Suzuki, H., Nagai, K., Akutsu, E., Yamaki, H. & Tanaka, N. On the mechanism of action of bleomycin. Strand scission of DNA caused by bleomycin and its binding to DNA in vitro. J. Antibiot. (Tokyo) 23, 473-480 (1970).
38. Iqbal, Z. M., Kohn, K. W., Ewig, R. A. & Fornace, A. J. Jr. Single-strand scission and repair of DNA in mammalian cells by bleomycin. Cancer Res. 36, 3834-3838 (1976).
39. Moore, C. W. & Little, J. B. Rapid and slow DNA rejoining in nondividing human diploid fibroblasts treated with bleomycin and ionizing radiation. Cancer Res. 45, 1982-1986 (1985).
40. Coogan, T. P., Rosenblum, I. Y. & Barsotti, D. A. Bleomycin-induced DNA-strand damage in isolated male germ cells. Mutat. Res. 162, 215-218 (1986).
41. Kuo, M. T. Preferential damage of active chromatin by bleomycin. Cancer Res. 41, 2439-2443 (1981).
42. 125IdUnd. Int. J. Radiat. Biol. 64, 349-358 (1993).
43. Xu, Y. J., Kim, E. Y. & Demple, B. Excision of C-4′-oxidized deoxyribose lesions from double-stranded DNA by human apurinic/apyrimidinic endonuclease (Ape1 protein) and DNA polymerase β. J. Biol. Chem. 273, 28837-28844 (1998).
44. Suh, D., Wilson, D. M. 3rd & Povirk, L. F. 3′-phosphodiesterase activity of human apurinic/apyrimidinic endonuclease at DNA double-strand break ends. Nucleic Acids Res. 25, 2495-2500 (1997).
45. Chaudhry, M. A., Dedon, P. C., Wilson, D. M., 3rd, Demple, B. & Weinfeld, M. Removal by human apurinic/apyrimidinic endonuclease 1 (Ape 1) and Escherichia coli exonuclease III of 3′-phosphoglycolates from DNA treated with neocarzinostatin, calicheamicin, and γ-radiation. Biochem. Pharmacol. 57, 531-538 (1999).
46. Parsons, J. L., Dianova, II & Dianov, G. L. APE1 is the major 3′-phosphoglycolate activity in human cell extracts. Nucleic Acids Res 32, 3531-3536 (2004).
47. Inamdar, K. V. et al. Conversion of phosphoglycolate to phosphate termini on 3′ overhangs of DNA double strand breaks by the human tyrosyl-DNA phosphodiesterase hTdp1. J. Biol. Chern. 277, 27162-27168 (2002).
48. Pelletier, H., Sawaya, M. R., Wolfle, W., Wilson, S. H. & Kraut, J. Crystal structures of human DNA polymerase β complexed with DNA: implications for catalytic mechanism, processivity, and fidelity. Biochemistry 35, 12742-12761 (1996).
49. Robertson, K. A. et al. Altered expression of Ape1/ref- f in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation. Cancer Res. 61, 2220-2225 (2001). Upregulation of APE1 is correlated with resistance of bleomycin in germ-cell tumours, indicating a role of APE1 in processing bleomycin-induced DNA lesions.
50. Ramana, C. V., Boldogh, I., Izumi, T. & Mitra, S. Activation of apurinic/apyrimidinic endonuclease in human cells by reactive oxygen species and its correlation with their adaptive response to genotoxicity of free radicals. Proc. Natl Acad. Sci. USA 95, 5061-5066 (1998).
51. He, Y. H., et al. Expression of yeast apurinic/apyrimidinic endonuclease (APN1) protects lung epithelial cells from bleomycin toxicity. Am. J. Respir. Cell. Mol. Biol. 25, 692-698 (2001).
52. Sun, D. A., Deng, J. Z., Starck, S. R. & Hecht, S. M. Mispyric acid, a new monocyclic titerpenoid with a novel skeleton from Mischocarpus pyriformis that inhibits DNA polymerase β. J. Am. Chem. Soc. 121, 6120-6124 (1999).
53. Li, S. S., Gao, Z., Feng, X., Jones, S. H. & Hecht, S. M. Plant sterols as selective DNA polymerase β lyase inhibitors and potentiators of bleomycin cytotoxicity. Bioorg. Med. Chem. 12, 4253-4258 (2004).
54. Valerie, K. & Povirk, L. F. Regulation and mechanisms of mammalian double-strand break repair. Oncogene 22, 5792-5812 (2003).
55. Sancar, A., Lindsey-Boltz, L. A., Unsal-Kacmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Am. Rev. Biochem. 73, 39-85 (2004).
56. Povirk, L. F., Bennett, R. A., Wang, P., Swerdlow, P. S. & Austin, M. J. Single base-pair deletions induced by bleomycin at potential double-strand cleavage sites in the aprt gene of stationary phase Chinese hamster ovary D422 cells. J. Mol. Biol. 243, 216-226 (1994). Mutagenic effects of bleomycin were examined. The results revealed predominant single-base deletions thought to result from the NHEJ of the blunt-ended dsDNA cleavage sites generated by bleomycin.
57. Koberle, B. & Speit, G. Molecular characterization of mutations at the hprt locus in V79 Chinese hamster cells induced by bleomycin in the presence of inhibitors of DNA repair. Mutat. Res. 249, 161-167 (1991).
58. Koberle, B., Haupter, S., Just, W. & Speit, G. Mutation screening of bleomycin-induced V79 Chinese hamster hprt mutants using multiplex polymerase chain reaction. Mutagenesis 6, 527-531 (1991).
59. Cairns, M. J. & Murray, V. Influence of chromafin structure on bleomycin-DNA interactions at base pair resolution in the human β-globin gene cluster. Biochemistry 35, 3753-8760 (1996).
60. Allio, T. & Preston, R. J. Increased sensitivity to chromatid aberration induction by bleomycin and neocarzinostatin results from alterations in a DNA damage response pathway. Mutat. Res. 453, 5-15 (2000).
61. Elson, A. et al. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc. Natl Acad. Sci. USA 93, 13084-13089 (1996).
62. Nelson, W. G. & Kastan, M. B. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol. Cell. Biol. 14, 1815-1823 (1994).
63. Muller, M. et al. Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. J. Clin. Invest. 99, 403-413 (1997).
64. Patel, V., Ensley, J. F., Gutkind, J. S. & Yeudall, W. A. Induction of apoptosis in head-and-neck squamous carcinoma cells by gamma-irradiation and bleomycin is p53-independent. Int. J. Cancer 88, 737-743 (2000).
65. Gimonet, D., Landais, E., Bobichon, H., Coninx, P. & Liautaud-Roger, F. Induction of apoptosis by bleomycin in p53-null HL-60 leukemia cells. Int. J. Oncol. 24, 313-319 (2004).
66. Mekid, H. et al. In vivo evolution of tumor cells after the generation of double-strand DNA breaks. Br. J. Cancer. 88, 1763-1771 (2003).
67. Gothelf, A., Mir, L. M. & Gehl, J. Electrochemotherapy: results of cancer treatment using enhanced delivery of bleomycin by electroporation. Cancer Treat. Rev. 29, 371-387 (2003).
68. Kanao, M., Tomita, S., Ishihara, S., Murakami, A. & Okada, H. Chelation of bleomycin with copper in vivo. Chemotherapy (Tokyo) 21, 1305-1310 (1973).
69. Rao, E. A., Saryan, L. A., Antholine, W. E. & Petering, D. H. Cytotoxic and antitumor properties of bleomycin and its metal complexes. J. Med. Chem. 23, 1310-1318 (1980).
70. Byrnes, R. W., Templin, J., Sem, D., Lyman, S. & Petering, D. H. Intracellular DNA strand scission and growth inhibition of Ehrlich ascites tumor cells by bleomycins. Cancer Res. 50, 5275-5286 (1990).
71. Roy, S. N. & Horwitz, S. B. Characterization of the association of radiolabeled bleomycin A2 with HeLa cells. Cancer Res. 44, 1541-1546 (1984).
72. Lyman, S. et al. Properties of the initial reaction of bleomycin and several of its metal complexes with Ehrlich cells. Cancer Res. 46, 4472-4476 (1986).
73. Kenani, A., Bailly, C., Houssin, R. & Henichart, J. P. Comparative subcellular distribution of the copper complexes of bleomycin-A2 and deglycobleomycin-A2. Anticancer Drugs 5, 199-201 (1994).
74. Pron, G., Belehradek, J. Jr. & Mir, L. M. Identification of a plasma membrane protein that specifically binds bleomycin. Biochem. Biophys. Res. Commun. 194, 333-337 (1993).
75. Pron, G. et al. Internalisation of the bleomycin molecules responsible for bleomycin toxicity: a receptor-mediated endocytosis mechanism. Biochem. Pharmacol. 57, 45-56 (1999).
76. Aouida, M. et al. Isolation and characterization of Saccharomyces cerevisae mutants with enhanced resistance to the anticancer drug bleomycin. Curr. Genet. 45, 265-272 (2004).
77. Aouida, M., Page, N., Leduc, A., Peter, M. & Ramotar, D. A genome-wide screen in Saccharomyces cerevisiae reveals altered transport as a mechanism of resistance to the anticancer drug bleomycin. Cancer Res. 64, 1102-1109 (2004).
78. Aouida, M., Leduc, A., Wang, H. & Ramotar, D. Characterization of a transport and detoxification pathway for the antitumor drug bleomycin in Saccharomyces cerevisiae. Biochem. J. 384, 47-58 (2004). Yeast mutants resistant to bleomycin were characterized and results indicated that proteins involved in polyamine uptake might be responsible for uptake of bleomycin into the cell. Using fluorescently labelled bleomycin, most of the bleomycin molecules were found to be sequestered in vacuoles.
79. Crooke, S. T. et al. Effects of variations in renal function on the clinical pharmacology of bleomycin administered as an IV bolus. Cancer Treat. Rep. 61, 1631-1636 (1977).
80. Seidel, S. D., Kan, H. L., Sott, W. T., Schisler, M. R. & Gollapudi, B. B. Identification of transcriptome profiles for the DNA-damaging agents bleomycin and hydrogen peroxide in L5178Y mouse lymphoma cells. Environ. Mol. Mutagen. 42, 19-25 (2003).
81. Kaminski, N. et al. Use of oligonucleotide microarrays to analyze gene expression patterns in pulmonary fibrosis reveals distinct patterns of gene expression in mice and humans. Chest 121, 31S-32S (2002).
82. Zuo, F. et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc. Natl Acad Sci. USA 99, 6292-6297 (2002).
83. Katsuma, S. et al. Molecular monitoring of bleomycin-induced pulmonary fibrosis by cDNA microarray-based gene expression profiling. Biochem. Biophys. Res. Commun. 288, 747-751 (2001).
84. Kaminski, N. et al. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis. Proc. Natl Acad. Sci. USA 97, 1778-1783 (2000).
85. Lazo, J. S. & Humphreys, C. J. Lack of metabolism as the biochemical basis of bleomycin-induced pulmonary toxicity. Proc. Natl Acad. Sci. USA 80, 3064-3068 (1983).
86. Umesawa, H., Hori, S., Sawa, T., Yoshioka, T. & Takeuchi, T. A bleomycin-inactivating enzyme in mouse liver. J. Antibiot. (Tokyo) 27, 419-424 (1974).
87. Sebti, S. M., Mignano, J. E., Jani, J. P., Srimatkandada, S. & Lazo, J. S. Bleomycin hydrolase: molecular cloning, sequencing, and biochemical studies reveal membership in the cysteine proteinase family. Biochemistry 28, 6544-6548 (1989).
88. Huang, C. H., Mirabelli, C. K., Jan, Y. & Crooke, S. T. Single-strand and double-strand deoxyribonucleic acid breaks produced by several bleomycin analogues. Biochemistry 20, 233-238 (1981).
89. Zou, Y., Fahmi, N. E., Vialas, C., Miller, G. M. & Hecht, S. M. Total synthesis of deamido bleomycin A2, the major catabolite of the antitumor agent bleomycin. J. Am. Chem. Sec. 124, 9476-9488 (2002).
90. Sebti, S. M., Jani, J. P., Mistry, J. S., Gorelik, E. & Lazo, J. S. Metabolic inactivation: a mechanism of human tumor resistance to bleomycin. Cancer Res. 51, 227-232 (1991).
91. Wang, H. & Ramotar, D. Cellular resistance to bleomycin in Saccharomyces cerevisiae is not affected by changes in bleomycin hydrolase levels. Biochem. Cell. Biol. 80, 789-796 (2002).
92. White, D. A. & Stover, D. E. Severe bleomycin-induced pneumonitis. Clinical features and response to corticosteroids. Chest 86, 723-728 (1984).
93. Du, L., Sanchez, C., Chen, M., Edwards, D. J. & Shen, B. The biosynthetic gene cluster for the antitumor drug bleomycin from Streptomyces verticillus ATCC15003 supporting functional interactions between nonribosomal peptide synthetases and a polyketide synthase. Chem. Biol. 7, 623-642 (2000). The genes involved in the biosynthesis of bleomycin were identified. Bleomycin was found to be synthesized by proteins found within nine non-ribosomal- polypeptide-synthetase modules and one polyketide-synthase module.
94. Du, L., Chen, M., Sanchez, C. & Shen, B. An oxidation domain in the BlmIII non-ribosomal peptide synthetase probably catalyzing thiazole formation in the biosynthesis of the anti-tumor drug bleomycin in Streptomyces verticillus ATCC15003. FEMS Microbiol. Lett. 189, 171-175 (2000).
95. Du, L., Chen, M., Zhang, Y. & Shen, B. BlmIII and BlmIV nonribosomal peptide synthetase-catalyzed biosynthesis of the bleomycin bithiazole moiety involving both in cis and in trans aminoacylation. Biochemistry 42, 9731-9740 (2003).
96. Schneider, T. L., Shen, B. & Walsh, G. T. Oxidase domains in epothilone and bleomycin biosynthesis: thiazoline to thiazole oxidation during chain elongation. Biochemistry 42, 9722-9730 (2003).
97. Hu, Y. & Walker, S. Remarkable structural similarities between diverse glycosyltransferases. Chem. Biol. 9, 1287-1296 (2002).
98. Losey, H. C. et al. Incorporation of glucose analogs by GtfE and GtfD from the vancomycin biosynthetic pathway to generate variant glycopeptides. Chem. Biol. 9, 1305-1314 (2002).
99. Walker, M. A. et al. Monoclonal antibody mediated intracellular targeting of tallysomycin S(10b). Bioorg. Med. Chem. Lett. 14, 4323-4327 (2004).
100. Magliozzo, R. S., Peisach, J. & Ciriolo, M. R. Transfer RNA is cleaved by activated bleomycin. Mol. Pharmacol. 35, 428-432 (1989).
101. Carter, B. J. et al. Site-specific cleavage of RNA by Fe(II)•bleomycin. Proc. Natl Acad. Sci. USA 87, 9373-9377 (1990).
102. Holmes, C. E., Abraham, A. T., Hecht, S. M., Florentz, C. & Giege, R. Fe bleomycin as a probe of RNA conformation. Nucleic Acids Res. 24, 3399-3406 (1996).
103. Abraham, A. T., Lin, J. J., Newton, D. L., Rybak, S. & Hecht, S. M. RNA cleavage and inhibition of protein synthesis by bleomycin. Chem. Biol. 10, 45-52 (2003).
104. Weterings, E. & van Gent, D. C. The mechanism of non-homologous end-joining: a synopsis of synapsis. DNA Repair 3, 1425-1435 (2004).
105. Sugiyama, M., Kumagai, T., Hayashida, M., Maruyama, M. & Matoba, Y. The 1.6-A crystal structure of the copper(II)-bound bleomycin complexed with the bleomycin-binding protein from bleomycin-producing Streptomyces verticillus. J. Biol. Chem. 277, 2311-2320 (2002).
106. Wu, W. et al. Studies of Co Bleomycin A2 green: Its detailed structural characterization by NMR and molecular modeling and its sequence-specific interaction with DNA oligonucleotides. J. Am. Chem. Soc. 118, 1268-1280 (1996).
107. Wu, J. C., Kozarich, J. W. & Stubbe, J. Mechanism of bleomycin: evidence for a rate-determining 4′-hydrogen abstraction from poly(dA-dU) associated with the formation of both free base and base propenal. Biochemistry 24, 7562-7568 (1985).
108. Rabow, L. E., Stubbe, J. & Kozarich, J. W. Identification and quantitation of the lesion accompanying base release in bleomycin-mediated DNA degradation. J. Am. Chem. Soc. 112, 3196-3203 (1990).
109. Giloni, L., Takeshita, M., Johnson, F., Iden, C. & Grollman, A. P. Bleomycin-induced strand-scission of DNA. J. Biol. Chem. 256, 8608-8615 (1981).
110. Burger, R. M., Berkowitz, A. R., Peisach, J. & Horwitz, S. B. Origin of malondialdehyde from DNA degraded by Fe(II)-bleomycin. J. Biol. Chem. 255, 11832-11838 (1930).
111. Povirk, L. F., Han, Y. H. & Steighner, R. J. Structure of bleomycin-induced DNA double-strand breaks: predominance of blunt ends and single-base 5′ extensions. Biochemistry 28, 5808-5814 (1989). Rules for the sequence specificity of bleomycin-mediated dsDNA cleavage are presented.
112. Zhou, B. B. & Elledge, S. J. The DNA damage response: putting checkpoints in perspective. Nature 408, 433-439 (2000).
113. Sugiura, Y., Ishízu, K. & Miyoshi, K. Studies of metallobleomycins by electronic spectroscopy, electron spin resonance spectroscopy, and potentiometric titration. J. Antibiot. (Tokyo) 32, 453-461 (1979).
114. Ehrenfeld, G. M. et al. Copper-dependent cleavage of DNA by bleomycin. Biochemistry 26, 931-942 (1987).
115. Ehrenfeld, G. M. et al. Copper(I)-bleomycin: structurally unique complex that mediates oxidative DNA strand scission. Biochemistry 24, 81-92 (1985).
116. Lee, J. W. et al. Implication of DNA polymerase (in alignment-based gap filling for nonhomologous DNA end joining in human nuclear extracts. J. Biol. Chem. 279, 805-811 (2004)