The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death
Identifieur interne : 001B52 ( Main/Exploration ); précédent : 001B51; suivant : 001B53The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death
Auteurs : En Huang [Canada] ; Dianbo Qu [Canada] ; Yi Zhang [Canada] ; Katerina Venderova [Canada] ; M. Emdadul Haque [Canada] ; Maxime W. C. Rousseaux [Canada] ; Ruth S. Slack [Canada] ; John M. Woulfe [Canada] ; David S. Park [Canada, Corée du Sud]Source :
- Nature Cell Biology [ 1465-7392 ] ; 2010-06.
Abstract
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.
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DOI: 10.1038/ncb2058
Affiliations:
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<front><div type="abstract" xml:lang="eng">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.</div>
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