title: HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism.
abstract: Upon severe DNA damage a cellular signalling network initiates a cell death response through activating tumour suppressor p53 in association with promyelocytic leukaemia (PML) nuclear bodies. The deacetylase Sirtuin 1 (SIRT1) suppresses cell death after DNA damage by antagonizing p53 acetylation. To facilitate efficient p53 acetylation, SIRT1 function needs to be restricted. How SIRT1 activity is regulated under these conditions remains largely unclear. Here we provide evidence that SIRT1 activity is limited upon severe DNA damage through phosphorylation by the DNA damage-responsive kinase HIPK2. We found that DNA damage provokes interaction of SIRT1 and HIPK2, which phosphorylates SIRT1 at Serine 682 upon lethal damage. Furthermore, upon DNA damage SIRT1 and HIPK2 colocalize at PML nuclear bodies, and PML depletion abrogates DNA damage-induced SIRT1 Ser682 phosphorylation. We show that Ser682 phosphorylation inhibits SIRT1 activity and impacts on p53 acetylation, apoptotic p53 target gene expression and cell death. Mechanistically, we found that DNA damage-induced SIRT1 Ser682 phosphorylation provokes disruption of the complex between SIRT1 and its activator AROS. Our findings indicate that phosphorylation-dependent restriction of SIRT1 activity by HIPK2 shapes the p53 response.
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Conrad
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Polonio-Vallon
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Meister
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Matt
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Bitomsky
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Herbel
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Liebl
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Greiner
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Kriznik
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schumacher
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Krieghoff-Henning
authors.affiliation: German Cancer Research Center (dkfz), Cellular Senescence Group, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors.forename: T G
authors.initials: TG
authors.lastname: Hofmann
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000235:genetics*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1