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Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death

Significance Activation of the cell death (apoptosis) program is a major principle of DNA-damaging cancer treatments including ionizing radiation and chemotherapeutic drug treatment. The protein kinase HIPK2 plays a key role in radiosensitivity and chemosensitivity. Here, we found that HIPK2 autointeracts and autophosphorylates after DNA damage. HIPK2 autophosphorylation is conserved in evolution and regulates its apoptosis-inducing activity by facilitating binding of the isomerase Pin1. Pin1 couples HIPK2 activation to its stabilization and is essential for DNA damage-induced apoptosis in cancer cells and in zebrafish. Our findings identify a mechanism linking HIPK2 activation to its stabilization and highlight a conserved function of HIPK2 and Pin1 in the DNA damage-induced apoptosis response. 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.