Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death
Excessive genome damage activates the apoptosis response. Protein kinase HIPK2 is a key regulator of DNA damage-induced apoptosis. Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and s...
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| Hauptverfasser: | , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
October 21, 2013
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| In: |
Proceedings of the National Academy of Sciences of the United States of America
Year: 2013, Jahrgang: 110, Heft: 45, Pages: E4203-E4212 |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.1310001110 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.1310001110 Verlag, lizenzpflichtig, Volltext: https://www.pnas.org/content/110/45/E4203 
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| Verfasserangaben: | Nadja Bitomsky, Elisa Conrad, Christian Moritz, Tilman Polonio-Vallon, Dirk Sombroek, Kathrin Schultheiss, Carolina Glas, Vera Greiner, Christoph Herbel, Fiamma Mantovani, Giannino del Sal, Francesca Peri, and Thomas G. Hofmann |
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| 245 | 1 | 0 | |a Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death |c Nadja Bitomsky, Elisa Conrad, Christian Moritz, Tilman Polonio-Vallon, Dirk Sombroek, Kathrin Schultheiss, Carolina Glas, Vera Greiner, Christoph Herbel, Fiamma Mantovani, Giannino del Sal, Francesca Peri, and Thomas G. Hofmann |
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| 520 | |a Excessive genome damage activates the apoptosis response. Protein kinase HIPK2 is a key regulator of DNA damage-induced apoptosis. Here, we deciphered the molecular mechanism of HIPK2 activation and show its relevance for DNA damage-induced apoptosis in cellulo and in vivo. HIPK2 autointeracts and site-specifically autophosphorylates upon DNA damage at Thr880/Ser882. Autophosphorylation regulates HIPK2 activity and mutation of the phosphorylation-acceptor sites deregulates p53 Ser46 phosphorylation and apoptosis in cellulo. Moreover, HIPK2 autophosphorylation is conserved between human and zebrafish and is important for DNA damage-induced apoptosis in vivo. Mechanistically, autophosphorylation creates a binding signal for the phospho-specific isomerase Pin1. Pin1 links HIPK2 activation to its stabilization by inhibiting HIPK2 polyubiquitination and modulating Siah-1-HIPK2 interaction. Concordantly, Pin1 is required for DNA damage-induced HIPK2 stabilization and p53 Ser46 phosphorylation and is essential for induction of apotosis both in cellulo and in zebrafish. Our results identify an evolutionary conserved mechanism regulating DNA damage-induced apoptosis. | ||
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