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@ARTICLE{Conrad:125656,
      author       = {E. Conrad$^*$ and T. Polonio-Vallon$^*$ and M. Meister$^*$
                      and S. Matt$^*$ and N. Bitomsky$^*$ and C. Herbel$^*$ and M.
                      Liebl$^*$ and V. Greiner$^*$ and B. Kriznik$^*$ and S.
                      Schumacher$^*$ and E. Krieghoff-Henning$^*$ and T.
                      Hofmann$^*$},
      title        = {{HIPK}2 restricts {SIRT}1 activity upon severe {DNA} damage
                      by a phosphorylation-controlled mechanism.},
      journal      = {Cell death and differentiation},
      volume       = {23},
      number       = {1},
      issn         = {1476-5403},
      address      = {Houndmills, Basingstoke},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2017-01782},
      pages        = {110 - 122},
      year         = {2016},
      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.},
      keywords     = {Carrier Proteins (NLM Chemicals) / TP53 protein, human (NLM
                      Chemicals) / Tumor Suppressor Protein p53 (NLM Chemicals) /
                      HIPK2 protein, human (NLM Chemicals) /
                      Protein-Serine-Threonine Kinases (NLM Chemicals) / SIRT1
                      protein, human (NLM Chemicals) / Sirtuin 1 (NLM Chemicals)},
      cin          = {A210},
      ddc          = {570},
      cid          = {I:(DE-He78)A210-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26113041},
      pmc          = {pmc:PMC4815982},
      doi          = {10.1038/cdd.2015.75},
      url          = {https://inrepo02.dkfz.de/record/125656},
}