Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway.

APE1/Ref-1 is an essential DNA repair/gene regulatory protein in mammals of which intracellular level significantly affects cellular sensitivity to genotoxicants. The apurinic/apyrimidinic endonuclease 1 (APE1) functions are altered by phosphorylation and acetylation. We here report that APE1 is also modified by ubiquitination. APE1 ubiquitination occurred specifically at Lys residues near ...
the N-terminus, and was markedly enhanced by mouse double minute 2 (MDM2), the major intracellular p53 inhibitor. Moreover, DNA-damaging reagents and nutlin-3, an inhibitor of MDM2-p53 interaction, increased APE1 ubiquitination in the presence of p53. Downmodulation of MDM2 increased APE1 level, suggesting that MDM2-mediated ubiquitination can be a signal for APE1 degradation. In addition, unlike the wild-type APE1, ubiquitin-APE1 fusion proteins were predominantly present in the cytoplasm. Therefore, monoubiquitination not only is a prerequisite for degradation, but may also alter the APE1 activities in cells. These results reveal a novel regulation of APE1 through ubiquitination.
Mesh Terms:
Animals, Cells, Cultured, DNA Repair, DNA-(Apurinic or Apyrimidinic Site) Lyase, HCT116 Cells, Humans, Mammals, Mice, NIH 3T3 Cells, Proto-Oncogene Proteins c-mdm2, Signal Transduction, Tumor Suppressor Protein p53, Ubiquitination
Oncogene
Date: Apr. 02, 2009
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