Down-regulation of topoisomerase I in mammalian cells following ionizing radiation

David A. Boothman, Nina Fukunaga, Meizhi Wang

Research output: Contribution to journalArticle

92 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4618-4626
Number of pages9
JournalCancer Research
Volume54
Issue number17
StatePublished - Sep 1 1994

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Type I DNA Topoisomerase
Ionizing Radiation
Down-Regulation
Cricetinae
DNA Repair
Enzymes
Adenosine Diphosphate
Single-Stranded DNA Breaks
DNA Breaks
Poly(ADP-ribose) Polymerases
Single-Stranded DNA
DNA Damage
X-Rays
Radiation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Boothman, D. A., Fukunaga, N., & Wang, M. (1994). Down-regulation of topoisomerase I in mammalian cells following ionizing radiation. Cancer Research, 54(17), 4618-4626.

Down-regulation of topoisomerase I in mammalian cells following ionizing radiation. / Boothman, David A.; Fukunaga, Nina; Wang, Meizhi.

In: Cancer Research, Vol. 54, No. 17, 01.09.1994, p. 4618-4626.

Research output: Contribution to journalArticle

Boothman, DA, Fukunaga, N & Wang, M 1994, 'Down-regulation of topoisomerase I in mammalian cells following ionizing radiation', Cancer Research, vol. 54, no. 17, pp. 4618-4626.
Boothman DA, Fukunaga N, Wang M. Down-regulation of topoisomerase I in mammalian cells following ionizing radiation. Cancer Research. 1994 Sep 1;54(17):4618-4626.
Boothman, David A. ; Fukunaga, Nina ; Wang, Meizhi. / Down-regulation of topoisomerase I in mammalian cells following ionizing radiation. In: Cancer Research. 1994 ; Vol. 54, No. 17. pp. 4618-4626.
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