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000125656 0247_ $$2ISSN$$a1476-5403
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000125656 041__ $$aeng
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000125656 1001_ $$0P:(DE-HGF)0$$aConrad, E.$$b0$$eFirst author
000125656 245__ $$aHIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism.
000125656 260__ $$aHoundmills, Basingstoke$$bNature Publishing Group$$c2016
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000125656 520__ $$aUpon 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.
000125656 536__ $$0G:(DE-HGF)POF3-311$$a311 - Signalling pathways, cell and tumor biology (POF3-311)$$cPOF3-311$$fPOF III$$x0
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000125656 650_7 $$2NLM Chemicals$$aCarrier Proteins
000125656 650_7 $$2NLM Chemicals$$aTP53 protein, human
000125656 650_7 $$2NLM Chemicals$$aTumor Suppressor Protein p53
000125656 650_7 $$0EC 2.7.1.-$$2NLM Chemicals$$aHIPK2 protein, human
000125656 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aProtein-Serine-Threonine Kinases
000125656 650_7 $$0EC 3.5.1.-$$2NLM Chemicals$$aSIRT1 protein, human
000125656 650_7 $$0EC 3.5.1.-$$2NLM Chemicals$$aSirtuin 1
000125656 7001_ $$0P:(DE-HGF)0$$aPolonio-Vallon, T.$$b1
000125656 7001_ $$0P:(DE-He78)c379b2d1f870219daf87c385a6310096$$aMeister, Matthias$$b2$$udkfz
000125656 7001_ $$0P:(DE-He78)ce86d7d02a229acfaca4b63f01a1171b$$aMatt, S.$$b3$$udkfz
000125656 7001_ $$0P:(DE-HGF)0$$aBitomsky, N.$$b4
000125656 7001_ $$0P:(DE-HGF)0$$aHerbel, C.$$b5
000125656 7001_ $$0P:(DE-He78)b78bad920e0726ad553428895cb9b6c3$$aLiebl, M.$$b6$$udkfz
000125656 7001_ $$0P:(DE-HGF)0$$aGreiner, V.$$b7
000125656 7001_ $$0P:(DE-He78)4d13282d8b2cf967d372c6846460ec3a$$aKriznik, B.$$b8$$udkfz
000125656 7001_ $$0P:(DE-He78)d70ddd73ff941566d830600443d2e69c$$aSchumacher, S.$$b9$$udkfz
000125656 7001_ $$0P:(DE-He78)8e2078af783ff2be822e7799c43bc86a$$aKrieghoff-Henning, E.$$b10$$udkfz
000125656 7001_ $$0P:(DE-He78)99ae95278bd95e30462a4fb2d12026c6$$aHofmann, Thomas$$b11$$eLast author$$udkfz
000125656 773__ $$0PERI:(DE-600)1496681-5$$a10.1038/cdd.2015.75$$gVol. 23, no. 1, p. 110 - 122$$n1$$p110 - 122$$tCell death and differentiation$$v23$$x1476-5403$$y2016
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