This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boothman, D. A. Articles by Wang, M. Search for Related Content PubMed PubMed Citation Articles by Boothman, D. A. Articles by Wang, M.

Down-Regulation of Topoisomerase I in Mammalian Cells following Ionizing Radiation¹

Department of Human Oncology and University of Wisconsin Comprehensive Cancer Center, K4/626 Clinical Science Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, Wisconsin 53792

Modulators of the Dna unwinding enzyme, topoisomerase I (Topo I), inhibit DNA repair and augment the lethal effects of X-rays and other agents that create breaks in DNA. To investigate the role of Topo I in DNA repair, we examined Topo I activity before and after X-irradiation using confluence-arrested hamster and human cells. Topo I activities were higher in unirradiated neoplastic compared to normal hamster or human cells. Following ionizing radiation, however, enzyme activities were dramatically down-regulated to a greater extent in tumor than in normal cells. The extent of Topo I down-regulation correlated to some extent with survival enhancement in irradiated cells. Enzyme activities were down-regulated within 5 min in hamster and human cells. Recovery of Topo I activities in X-irradiated hamster cells required 12 h, whereas irradiated human cells recovered in only 70 min. Decreased Topo I activity was also noted after UV irradiation. In contrast, Topo I protein and mRNA levels remained unchanged following radiation. Administration of 5 mM 3-aminobenzamide or 0.5 mM PD 128763, inhibitors of poly(ADP-ribose) transferase, prevented Topo I down-regulation in X-irradiated or UV-irradiated human or hamster cells. Thus, decreases in Topo I activity following DNA damage are likely caused by ADP-ribosylation of the enzyme. Down-regulation of Topo I may prevent its binding to single-stranded DNA nicks created by X-irradiation, allowing the DNA repair complex (which is concomitantly activated by ADP-ribosylation) access to these lesions.

¹ Supported by Grant PDT-413/DHP-90A (to D. A. B.) from the American Cancer Society.

² To whom requests for reprints should be addressed, at Department of Human Oncology and University of Wisconsin Comprehensive Cancer Center, K4/626 Clinical Science Center, University of Wisconsin-Madison, 600 Highland Avenue, Madison, Wisconsin 53792.

³ Present address: Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI 48109.

⁴ Present address: Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109.

Received 10/26/93. Accepted 7/ 5/94.

This article has been cited by other articles:

				C.-C. Kuo, J.-F. Liu, and J.-Y. Chang DNA Repair Enzyme, O6-Methylguanine DNA Methyltransferase, Modulates Cytotoxicity of Camptothecin-Derived Topoisomerase I Inhibitors J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 946 - 954. [Abstract] [Full Text] [PDF]

				T. M. C. Yung, S. Sato, and M. S. Satoh Poly(ADP-ribosyl)ation as a DNA Damage-induced Post-translational Modification Regulating Poly(ADP-ribose) Polymerase-1-Topoisomerase I Interaction J. Biol. Chem., September 17, 2004; 279(38): 39686 - 39696. [Abstract] [Full Text] [PDF]

				A. Y. Chen, S.-J. Shih, M. Hsiao, M. L. Rothenberg, and M. Prudhomme Induction of Radiosensitization by Indolocarbazole Derivatives: The Role of DNA Topoisomerase I Mol. Pharmacol., September 1, 2004; 66(3): 553 - 560. [Abstract] [Full Text] [PDF]

				T. M. C. Yung, M. Parent, E. L. Y. Ho, and M. S. Satoh Camptothecin-sensitive Relaxation of Supercoiled DNA by the Topoisomerase I-like Activity Associated with Poly(ADP-ribose) Polymerase-1 J. Biol. Chem., March 19, 2004; 279(12): 11992 - 11999. [Abstract] [Full Text] [PDF]

				H. Kohara, M. Tabata, K. Kiura, H. Ueoka, K. Kawata, M. Chikamori, K. Aoe, K. Chikamori, A. Matsushita, and M. Harada Synergistic Effects of Topoisomerase I Inhibitor, 7-ethyl-10-hydroxycamptothecin, and Irradiation in a Cisplatin-resistant Human Small Cell Lung Cancer Cell Line Clin. Cancer Res., January 1, 2002; 8(1): 287 - 292. [Abstract] [Full Text] [PDF]

				F. Cortes and N. Pastor Ionizing radiation damage repair: a role for topoisomerases? Mutagenesis, July 1, 2001; 16(4): 365 - 368. [Abstract] [Full Text] [PDF]

				A. Y. CHEN, P. B. SCRUGGS, L. GENG, M. L. ROTHENBERG, and D. E. HALLAHAN p53 and p21 Are Major Cellular Determinants for DNA Topoisomerase I-Mediated Radiation Sensitization in Mammalian Cells Ann. N.Y. Acad. Sci., December 1, 2000; 922(1): 298 - 300. [Full Text] [PDF]

				M. A. Johnson, P. E. Bryant, and N. J. Jones Isolation of camptothecin-sensitive Chinese hamster cell mutants: phenotypic heterogeneity within the ataxia telangiectasia-like XRCC8 (irs2) complementation group Mutagenesis, July 1, 2000; 15(4): 367 - 374. [Abstract] [Full Text] [PDF]

				C.-R. YANG, C. WILSON-VAN PATTEN, S. M. PLANCHON, S. M. WUERZBERGER-DAVIS, T. W. DAVIS, S. CUTHILL, S. MIYAMOTO, and D. A. BOOTHMAN Coordinate modulation of Sp1, NF-kappa B, and p53 in confluent human malignant melanoma cells after ionizing radiation FASEB J, February 1, 2000; 14(2): 379 - 390. [Abstract] [Full Text]

				H. M. Smith and A. J. Grosovsky PolyADP-ribose-mediated regulation of p53 complexed with topoisomerase I following ionizing radiation Carcinogenesis, August 1, 1999; 20(8): 1439 - 1444. [Abstract] [Full Text] [PDF]

				D. A Boothman, E. Odegaard, C.-R. Yang, K. Hosley, and M. S Mendonca Molecular analyses of adaptive survival responses (ASRs): role of ASRs in radiotherapy Human and Experimental Toxicology, August 1, 1998; 17(8): 448 - 453. [Abstract] [PDF]

				J. L. Nitiss, K. C. Nitiss, A. Rose, and J. L. Waltman Overexpression of Type I Topoisomerases Sensitizes Yeast Cells to DNA Damage J. Biol. Chem., July 6, 2001; 276(28): 26708 - 26714. [Abstract] [Full Text] [PDF]