Two essential but distinct functions of the mammalian abasic endonuclease

Tadahide Izumi, David B. Brown, C. V. Naidu, Kishor K. Bhakat, Mark A. MacInnes, Hiroshi Saito, David J. Chen, Sankar Mitra

Research output: Contribution to journalArticle

169 Citations (Scopus)

Abstract

The mammalian abasic endonuclease, APE1, has two distinct roles in the repair of oxidative DNA damage and in gene regulation. Here we show that both functions are essential for cell survival. Deletion of the APE1 gene causes embryonic lethality in mice, and no nullizygous embryo fibroblasts have been isolated. We have now established nullizygous embryo fibroblast lines from APE1-/- mouse embryos that are transgenic with the "floxed" human APE1 (hAPE1) gene. Removal of hAPE1 by Cre expression through nuclear microinjection elicited apoptosis in these cells within 24 h, which was blocked by coinjection of the wild-type hAPE1 gene. In contrast, mutant hPE1 alleles, lacking either the DNA repair or acetylation-mediated gene regulatory function, could not prevent apoptosis, although the combination of these two mutants complemented APE deficiency induced by Cre. These results indicate that distinct and separable functions of APE1 are both essential for mammalian cells even in vitro and provide the evidence that mammalian cells, unlike yeast or Escherichia coli, absolutely require APE for survival, presumably to protect against spontaneous oxidative DNA damage.

Original languageEnglish (US)
Pages (from-to)5739-5743
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number16
DOIs
StatePublished - Apr 19 2005

Fingerprint

Endonucleases
Embryonic Structures
DNA Damage
Fibroblasts
Apoptosis
Genes
Gene Deletion
Microinjections
Regulator Genes
Acetylation
DNA Repair
Transgenic Mice
Cell Survival
Yeasts
Alleles
Escherichia coli
Survival

Keywords

  • Base excision repair
  • Conditional gene inactivation
  • DNA repair
  • Endogenous DNA damage

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Izumi, T., Brown, D. B., Naidu, C. V., Bhakat, K. K., MacInnes, M. A., Saito, H., ... Mitra, S. (2005). Two essential but distinct functions of the mammalian abasic endonuclease. Proceedings of the National Academy of Sciences of the United States of America, 102(16), 5739-5743. https://doi.org/10.1073/pnas.0500986102

Two essential but distinct functions of the mammalian abasic endonuclease. / Izumi, Tadahide; Brown, David B.; Naidu, C. V.; Bhakat, Kishor K.; MacInnes, Mark A.; Saito, Hiroshi; Chen, David J.; Mitra, Sankar.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 16, 19.04.2005, p. 5739-5743.

Research output: Contribution to journalArticle

Izumi, T, Brown, DB, Naidu, CV, Bhakat, KK, MacInnes, MA, Saito, H, Chen, DJ & Mitra, S 2005, 'Two essential but distinct functions of the mammalian abasic endonuclease', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 16, pp. 5739-5743. https://doi.org/10.1073/pnas.0500986102
Izumi, Tadahide ; Brown, David B. ; Naidu, C. V. ; Bhakat, Kishor K. ; MacInnes, Mark A. ; Saito, Hiroshi ; Chen, David J. ; Mitra, Sankar. / Two essential but distinct functions of the mammalian abasic endonuclease. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 16. pp. 5739-5743.
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