The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death
Identifieur interne : 000509 ( Main/Exploration ); précédent : 000508; suivant : 000510The 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]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
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C." last="Rousseaux">Maxime W. C. Rousseaux</name></author><author><name sortKey="Slack, Ruth S" sort="Slack, Ruth S" uniqKey="Slack R" first="Ruth S." last="Slack">Ruth S. Slack</name></author><author><name sortKey="Woulfe, John M" sort="Woulfe, John M" uniqKey="Woulfe J" first="John M." last="Woulfe">John M. Woulfe</name></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:F537E4A9D0B2B0CEC6E764E3C7EF4B9B0C11B0EB</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1038/ncb2058</idno><idno type="url">https://api.istex.fr/document/F537E4A9D0B2B0CEC6E764E3C7EF4B9B0C11B0EB/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">001865</idno><idno type="wicri:Area/Main/Curation">001619</idno><idno type="wicri:Area/Main/Exploration">000509</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death</title><author><name sortKey="Huang, En" sort="Huang, En" uniqKey="Huang E" first="En" last="Huang">En Huang</name><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Cellular Molecular Medicine, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation><affiliation><wicri:noCountry code="no comma">These authors contributed equally to this work.</wicri:noCountry></affiliation></author><author><name sortKey="Qu, Dianbo" sort="Qu, Dianbo" uniqKey="Qu D" first="Dianbo" last="Qu">Dianbo Qu</name><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Cellular Molecular Medicine, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation><affiliation><wicri:noCountry code="no comma">These authors contributed equally to this work.</wicri:noCountry></affiliation></author><author><name sortKey="Zhang, Yi" sort="Zhang, Yi" uniqKey="Zhang Y" first="Yi" last="Zhang">Yi Zhang</name><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Cellular Molecular Medicine, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Venderova, Katerina" sort="Venderova, Katerina" uniqKey="Venderova K" first="Katerina" last="Venderova">Katerina Venderova</name><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Cellular Molecular Medicine, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Haque, M Emdadul" sort="Haque, M Emdadul" uniqKey="Haque M" first="M. Emdadul" last="Haque">M. Emdadul Haque</name><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Cellular Molecular Medicine, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Rousseaux, Maxime W C" sort="Rousseaux, Maxime W C" uniqKey="Rousseaux M" first="Maxime W. C." last="Rousseaux">Maxime W. C. Rousseaux</name><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Cellular Molecular Medicine, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Slack, Ruth S" sort="Slack, Ruth S" uniqKey="Slack R" first="Ruth S." last="Slack">Ruth S. Slack</name><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Cellular Molecular Medicine, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Woulfe, John M" sort="Woulfe, John M" uniqKey="Woulfe J" first="John M." last="Woulfe">John M. Woulfe</name><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Departments of Pathology and Laboratory Medicine and of Biochemistry, University of Ottawa, Cancer Research Group, OHRI. Ottawa Hospital, Civic Campus, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Cellular Molecular Medicine, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation><affiliation><wicri:noCountry code="subField">Busan 609 735 South Korea</wicri:noCountry></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Canada</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Nature Cell Biology</title><idno type="ISSN">1465-7392</idno><idno type="eISSN">1476-4679</idno><imprint><publisher>Nature Publishing Group</publisher><date type="published" when="2010-06">2010-06</date><biblScope unit="volume">12</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="563">563</biblScope><biblScope unit="page" to="571">571</biblScope></imprint><idno type="ISSN">1465-7392</idno></series><idno type="istex">F537E4A9D0B2B0CEC6E764E3C7EF4B9B0C11B0EB</idno><idno type="DOI">10.1038/ncb2058</idno><idno type="ArticleID">ncb2058</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1465-7392</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><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></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Huang, En" sort="Huang, En" uniqKey="Huang E" first="En" last="Huang">En Huang</name></noRegion><name sortKey="Haque, M Emdadul" sort="Haque, M Emdadul" uniqKey="Haque M" first="M. Emdadul" last="Haque">M. Emdadul Haque</name><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S." last="Park">David S. Park</name><name sortKey="Qu, Dianbo" sort="Qu, Dianbo" uniqKey="Qu D" first="Dianbo" last="Qu">Dianbo Qu</name><name sortKey="Rousseaux, Maxime W C" sort="Rousseaux, Maxime W C" uniqKey="Rousseaux M" first="Maxime W. C." last="Rousseaux">Maxime W. C. Rousseaux</name><name sortKey="Slack, Ruth S" sort="Slack, Ruth S" uniqKey="Slack R" first="Ruth S." last="Slack">Ruth S. Slack</name><name sortKey="Venderova, Katerina" sort="Venderova, Katerina" uniqKey="Venderova K" first="Katerina" last="Venderova">Katerina Venderova</name><name sortKey="Woulfe, John M" sort="Woulfe, John M" uniqKey="Woulfe J" first="John M." last="Woulfe">John M. Woulfe</name><name sortKey="Zhang, Yi" sort="Zhang, Yi" uniqKey="Zhang Y" first="Yi" last="Zhang">Yi Zhang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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