HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism.
HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism.
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DOI：
10.1038/cdd.2015.75
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发表时间：
2016-01
影响因子：
12.4
通讯作者：
Hofmann TG
中科院分区：
文献类型：
--
作者：
Conrad E;Polonio-Vallon T;Meister M;Matt S;Bitomsky N;Herbel C;Liebl M;Greiner V;Kriznik B;Schumacher S;Krieghoff-Henning E;Hofmann TG
在严重DNA损伤时，细胞信号传导网络通过激活与早幼粒细胞白血病（PML）核小体相关的肿瘤抑制因子p53启动细胞死亡应答。去乙酰化酶Sirtuin 1（SIRT 1）通过拮抗p53乙酰化抑制DNA损伤后的细胞死亡。为了促进有效的p53乙酰化，需要限制SIRT1功能。在这些条件下，SIRT1活性是如何调节的，目前还不清楚。在这里，我们提供的证据表明，SIRT1的活性是有限的严重DNA损伤，通过磷酸化的DNA损伤反应激酶HIPK2。我们发现，DNA损伤引起SIRT1和HIPK2的相互作用，在致命损伤后，HIPK2使SIRT1在丝氨酸682处磷酸化。此外，在DNA损伤时，SIRT1和HIPK2共定位于PML核体，并且PML耗竭消除DNA损伤诱导的SIRT1 Ser682磷酸化。我们发现Ser682磷酸化抑制SIRT1活性并影响p53乙酰化、凋亡p53靶基因表达和细胞死亡。从机制上讲，我们发现DNA损伤诱导的SIRT1 Ser682磷酸化引起SIRT1及其激活剂AROS之间的复合物的破坏。我们的研究结果表明，HIPK2对SIRT1活性的磷酸化依赖性限制塑造了p53反应。
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.