Apurinic/Apyrimidinic Endonuclease (APE/REF-1) Haploinsufficient Mice Display Tissue-specific Differences in DNA Polymerase β-Dependent Base Excision Repair

Julian J. Raffoul, Diane C. Cabelof, Jun Nakamura, Lisiane B. Meira, Errol C. Friedberg, Ahmad R. Heydari

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Abstract

Apurinic/apyrimidinic (AP) endonuclease (APE) is a multifunctional protein possessing both DNA repair and redox regulatory activities. In base excision repair (BER), APE is responsible for processing spontaneous, chemical, or monofunctional DNA glycosylase-initiated AP sites via its 5′-endonuclease activity and 3′-"end-trimming" activity when processing residues produced as a consequence of bifunctional DNA glycosylases. In this study, we have fully characterized a mammalian model of APE haploinsufficiency by using a mouse containing a heterozygous gene-targeted deletion of the APE gene (Apex+/-). Our data indicate that Apex+/- mice are indeed APE-haploinsufficient, as exhibited by a 40-50% reduction (p < 0.05) in APE mRNA, protein, and 5′-endonuclease activity in all tissues studied. Based on gene dosage, we expected to see a concomitant reduction in BER activity; however, by using an in vitro G:U mismatch BER assay, we observed tissue-specific alterations in monofunctional glycosylase-initiated BER activity, e.g. liver (35% decrease, p < 0.05), testes (55% increase, p < 0.05), and brain (no significant difference). The observed changes in BER activity correlated tightly with changes in DNA polymerase β and AP site DNA binding levels. We propose a mechanism of BER that may be influenced by the redox regulatory activity of APE, and we suggest that reduced APE may render a cell/tissue more susceptible to dysregulation of the polymerase β-dependent BER response to cellular stress.

Original languageEnglish (US)
Pages (from-to)18425-18433
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number18
DOIs
StatePublished - Apr 30 2004

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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