4.5 Article

The VRK1 chromatin kinase regulates the acetyltransferase activity of Tip60/KAT5 by sequential phosphorylations in response to DNA damage

出版社

ELSEVIER
DOI: 10.1016/j.bbagrm.2022.194887

关键词

Tip60; VRK1; Phosphorylation; Acetylation; DNA damage; Histone

资金

  1. Agencia Estatal de Investigacion-Ministerio de Ciencia e Innovacion-FEDER [RED2018-102801-T, PID2019-105610RB-I00]
  2. Consejeria de Educacion de la Junta de Castilla y Leon-ERDF [CSI264P20, CLC-2017-01]
  3. Ministerio de Educacion predoctoral fellowship [FPU16/01883]
  4. Consejeria de Educacion-Junta de Castilla y Leon-Fondo Social Europeo [CSI004-18]
  5. Agencia Estatal de Investigacion-MINECO predoctoral fellowship [BES-2017-080543]

向作者/读者索取更多资源

This study reveals the role of VRK1 chromatin kinase in the activation of Tip60 and the cooperation between VRK1 and DNA-PK in Tip60 phosphorylation. T158 phosphorylation protects Tip60 from degradation, promotes its recruitment to chromatin, and is necessary for its full activity. S199 phosphorylation directly facilitates Tip60 autoacetylation. These findings are important for understanding the regulatory mechanisms of chromatin remodeling in the DNA damage response.
The regulation of histone epigenetic modifications mediates the adaptation of chromatin to different biological processes. DNA damage causes a local relaxation of chromatin associated to histone H4 acetylation in K16, mediated by Tip60/KAT5. In this work, we have studied the role that the VRK1 chromatin kinase plays on the activation of Tip60 during this process. In the DNA damage response induced by doxorubicin, VRK1 directly phosphorylates Tip60. However, the phosphorylated Tip60 residues and their functional roles are unknown. In DDR, we have identified these two Tip60 phosphorylated residues and the cooperation of the participating ki-nases. The T158 phosphorylation, mediated by VRK1, is early and transient, preceding that of S199, which is more sustained in time, and mediated by DNA-PK. The role of each phosphorylated residues was determined by using phosphomimetic and phosphonull mutants and their combination. T158 phosphorylation protects Tip60 from ubiquitin-mediated degradation, promotes its recruitment to chromatin from the nucleoplasm, and is necessary for its full trans-acetylase activity. The phosphorylation in S199 by DNA-PK directly facilitates Tip60 autoacetylation, but it is not enough for trans-acetylation of two of its targets, histone H4 and ATM, which re-quires a double phosphorylation of Tip60 in T158 and S199. DNA-PK inhibitors block the phosphorylation of S199. We propose a model in which the cooperation between VRK1 and DNA-PK mediates the sequential phosphorylation of Tip60/KAT5, and contributes to the recruitment of this protein to initiate the sequential remodeling of chromatin in DDR. Both proteins are candidates for novel synthetic lethality strategies in cancer treatment.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.5
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据