The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death

En Huang, Dianbo Qu, Yi Zhang, Katerina Venderova, M. Emdadul Haque, Maxime W.C. Rousseaux, Ruth S. Slack, John M. Woulfe, David S. Park

Research output: Contribution to journalArticlepeer-review

99 Citations (Scopus)


Accumulating evidence suggests that deregulated cyclin-dependent kinase 5 (Cdk5) plays a critical part in neuronal death. However, the pathogenic targets of Cdk5 are not fully defined. Here we demonstrate that the Cdk5 activator p35 interacts directly with apurinic/apyrimidinic endonuclease 1 (Ape1), a protein crucial for base excision repair (BER) following DNA damage. Cdk5 complexes phosphorylate Ape1 at Thr 232 and thereby reduces its apurinic/apyrimidinic (AP) endonuclease activity. Ape1 phosphorylation is dependent on Cdk5 in in vitro and in vivo. The reduced endonuclease activity of phosphorylated Ape1 results in accumulation of DNA damage and contributes to neuronal death. Overexpression of Ape1WT and Ape1T232A, but not the phosphorylation mimic Ape1T232E, protects neurons against MPP +/MPTP. Loss of Ape1 sensitizes neurons to death. Importantly, increased phosphorylated Ape1 was also observed in post-mortem brain tissue from patients with Parkinson's and Alzheimer's diseases, suggesting a potential link between Ape1 phosphorylation and the pathogenesis of neurodegenerative diseases.

Original languageEnglish
Pages (from-to)563-571
Number of pages9
JournalNature Cell Biology
Issue number6
Publication statusPublished - Jun 2010
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology


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