Effects of Ape1 overexpression on cellular resistance to DNA-damaging and anticancer agents

L. J. Schild, K. W. Brookman, L. H. Thompson, D. M. Wilson

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

In vitro biochemical studies indicate that Ape1 is the major mammalian enzyme responsible for repairing abasic lesions in DNA and a significant factor in the processing of specific 3′-replication-blocking termini. Toward addressing the role of Ape1 in cellular resistance to specific DNA-damaging and anticancer agents, we constructed a chinese hamster ovary (CHO) cell line, AA8-Ape1, that exhibits a 7-fold higher Ape1-dependent nuclease activity; this overexpression is abolished upon exposure to tetracycline (Tc). In comparison to the AA8 parental control, our data indicates that Ape1 activity is not rate-limiting for the repair of cytotoxic damages induced by the alkylating agent methyl methanesulfonate (MMS), the oxidizing agent hydrogen peroxide (H2O2), or ionizing radiation (IR). AA8-Ape1 cells did exhibit increased resistance to bleomycin following a chronic 3-day exposure, but not to more acute challenges of 1 h. Most notably, the AA8-Ape1 line displayed ∼ 1.7-fold elevated resistance to the replication-blocking nucleoside analog dioxolane cytidine (L-OddC); this improved resistance was abrogated by the addition of Tc to the medium. These studies demonstrate that Ape1 is not rate-limiting in the repair of MMS- or H2O2-induced DNA damage, that Ape1 may dictate the sensitivity of bleomycin, depending on dosing scheme, and for the first time, that Ape1 can influence cellular resistance to the anticancer/antiviral antimetabolite L-OddC.

Original languageEnglish (US)
Pages (from-to)253-262
Number of pages10
JournalSomatic Cell and Molecular Genetics
Volume25
Issue number5-6
DOIs
StatePublished - Nov 1999
Externally publishedYes

Keywords

  • Antimetabolite/nucleoside analog
  • Antiviral/anticancer agent
  • Ape1
  • Base excision repair
  • Cellular resistance
  • L-OddC

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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