1. ¹Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland
2. ²Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
3. ³Institute of Biochemistry, Justus-Liebig-University, Giessen, Germany
4. ⁴Novartis Pharma AG WKL-125.7.04, Basel, Switzerland
5. ⁵Institute for Biomedical Engineering, University and ETH Zürich, Zürich, Switzerland

Correspondence: Dr ML Schmitz, Institute of Biochemistry, Biochemical Institute, Justus-Liebig-University, Friedrichstrasse 24, Giessen 35392, Germany. E-mail: lienhard.schmitz@biochemie.med.uni-giessen.de

Received 5 August 2008; Revised 15 October 2008; Accepted 20 October 2008; Published online 17 November 2008.

Abstract

The promyelocytic leukemia (PML) tumor suppressor protein, a central regulator of cell proliferation and apoptosis, is frequently fused to the retinoic acid receptor- (RAR) in acute PML. Here we show the interaction of PML with another tumor suppressor protein, the serine/threonine kinase homeodomain-interacting protein kinase (HIPK2). In response to DNA damage, HIPK2 phosphorylates PML at serines 8 and 38. Although HIPK2-mediated phosphorylation of PML occurs early during the DNA damage response, the oncogenic PML-RAR fusion protein is phosphorylated with significantly delayed kinetics. DNA damage or HIPK2 expression leads to the stabilization of PML and PML-RAR proteins. The N-terminal phosphorylation sites contribute to the DNA damage-induced PML SUMOylation and are required for the ability of PML to cooperate with HIPK2 for the induction of cell death.