Apurinic/apyrimidinic endonuclease (APE/REF-1) haploinsufficient mice display tissue-specific differences in DNA polymerase beta-dependent base excision repair

J Biol Chem. 2004 Apr 30;279(18):18425-33. doi: 10.1074/jbc.M313983200. Epub 2004 Feb 18.


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 beta 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 beta-dependent BER response to cellular stress.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Pair Mismatch
  • Binding Sites
  • Brain / metabolism
  • DNA Polymerase beta / metabolism*
  • DNA Repair*
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / deficiency*
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / genetics
  • Haplotypes
  • Heterozygote
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Organ Specificity
  • Oxidation-Reduction
  • Testis / metabolism


  • DNA Polymerase beta
  • Apex1 protein, mouse
  • DNA-(Apurinic or Apyrimidinic Site) Lyase