HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation

F. De Nicola, V. Catena, C. Rinaldo, T. Bruno, S. Iezzi, C. Sorino, A. Desantis, S. Camerini, M. Crescenzi, A. Floridi, C. Passananti, S. Soddu, M. Fanciulli

Research output: Contribution to journalArticle

Abstract

Che-1/AATF is an RNA polymerase II-binding protein that is involved in the regulation of gene transcription, which undergoes stabilization and accumulation in response to DNA damage. We have previously demonstrated that following apoptotic induction, Che-1 protein levels are downregulated through its interaction with the E3 ligase HDM2, which leads to Che-1 degradation by ubiquitylation. This interaction is mediated by Pin1, which determines a phosphorylation-dependent conformational change. Here we demonstrate that HIPK2, a proapoptotic kinase, is involved in Che-1 degradation. HIPK2 interacts with Che-1 and, upon genotoxic stress, phosphorylates it at specific residues. This event strongly increases HDM2/Che-1 interaction and degradation of Che-1 protein via ubiquitin-dependent proteasomal system. In agreement with these findings, we found that HIPK2 depletion strongly decreases Che-1 ubiquitylation and degradation. Notably, Che-1 overexpression strongly counteracts HIPK2-induced apoptosis. Our results establish Che-1 as a new HIPK2 target and confirm its important role in the cellular response to DNA damage.

Original languageEnglish
Article numbere1414
JournalCell Death and Disease
Volume5
Issue number9
DOIs
Publication statusPublished - Jan 1 2014

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience
  • Medicine(all)

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    De Nicola, F., Catena, V., Rinaldo, C., Bruno, T., Iezzi, S., Sorino, C., Desantis, A., Camerini, S., Crescenzi, M., Floridi, A., Passananti, C., Soddu, S., & Fanciulli, M. (2014). HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation. Cell Death and Disease, 5(9), [e1414]. https://doi.org/10.1038/cddis.2014.381