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PML Is Required for Homeodomain-interacting Protein Kinase 2 (HIPK2)-mediated p53 Phosphorylation and Cell Cycle Arrest but Is Dispensable for the Formation of HIPK Domains¹

Division of Immunochemistry, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany [A. M., S. R., E. K., W. D.]; University of Bern, Department of Chemistry and Biochemistry, CH-3012 Bern, Switzerland [A. M., M. L. S.]; and Department of General Virology, Heinrich-Pette-Institut für experimentelle Virologie und Immunologie, 20251 Hamburg, Germany [H. S., T. G. H., H. W.]

Here we demonstrate that endogenous human homeodomain-interacting protein kinase (HIPK) 2 and the highly homologous kinase HIPK3 are found in a novel subnuclear domain, the HIPK domains. These are distinct from other subnuclear structures such as Cajal bodies and nucleoli and show only a partial colocalization with promyelocytic leukemia (PML) nuclear bodies (PML-NBs). A kinase inactive HIPK2 point mutant is localized in the nucleoplasm. The occurrence of HIPK domains in PML^-/- fibroblasts reveals their independence from the PML protein. HIPK2 can be almost completely recruited to PML-NBs by the PML isoform PML IV, but not by PML-III. PML IV-mediated recruitment of HIPK2 does not rely on its kinase function and also occurs in PML^-/- fibroblasts, showing that this PML isoform is sufficient for recruitment of HIPK2. Whereas the architecture of HIPK domains is PML independent, HIPK2-mediated enhancement of p53-dependent transcription, p53 serine 46 phosphorylation and the antiproliferative function of HIPK2 strictly rely on the presence of PML.

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