title: HIPK2 sustains apoptotic response by phosphorylating Che-1/AATF and promoting its degradation.
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.
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: De Nicola
authors.affiliation: 1] Epigenetics Laboratory, Regina Elena National Cancer Institute, Rome, Italy [2] Department of Biothecnological and Applied Clinical Science, University of L'Aquila, Aquila, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Catena
authors.affiliation: 1] Institute of Molecular Biology and Pathology, National Research Council (CNR), c/o Sapienza University of Rome, Rome, Italy [2] Experimental Oncology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Rinaldo
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Bruno
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Iezzi
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Sorino
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Desantis
authors.affiliation: Department of Cell Biology and Neurosciences, Higher Institute of Health (ISS), Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Camerini
authors.affiliation: Department of Cell Biology and Neurosciences, Higher Institute of Health (ISS), Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Crescenzi
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Floridi
authors.affiliation: Institute of Molecular Biology and Pathology, National Research Council (CNR), c/o Sapienza University of Rome, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Passananti
authors.affiliation: Experimental Oncology Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Soddu
authors.affiliation: Epigenetics Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fanciulli
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C402637:AATF protein, human; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases