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The molecular basis and regulation of the DNA damage-induced nuclear export of the human MacroD2 protein

DNA损伤诱导人MacroD2蛋白核输出的分子基础和调控

基本信息

批准号：
244862758
负责人：
Dr. Gyula Timinszky
金额：
--
依托单位：
Szeged Biological Research Centre (BRC)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/244862758?language=en
关键词：
molecular basis regulation DNA damage

项目摘要

Cells rapidly respond to DNA damage by activating vital signaling and repair pathways. The orchestration of cellular events often involves the modulation of protein traffic between nucleus and cytoplasm by post-translational modifications. Phosphorylation and poly-ADP-ribosylation (PARylation) constitute major signaling pathways regulating protein function upon DNA damage. Significantly, PARylation is an important regulator of double-strand break repair choice between homologous recombination and non-homologous end-joining. While this crosstalk is of clinical relevance, its molecular basis is poorly understood. MacroD2, one of the newly identified terminal ADP-ribosylhydrolases fully reversing protein PARylation, emerges as an important regulator of the crosstalk between phosphorylation and PARylation. MacroD2 rapidly recruits to damage sites upon PARylation and removes the terminal ADP-ribose unit from proteins, but is exported from the nucleus in response to activation of DNA damage response (DDR) kinases (PIKKs). Using a combination of live-cell imaging, biochemical assays and high-content siRNA-based screening, the proposed project will identify the molecular basis and regulation of this novel DNA damage-induced export mechanism. Furthermore, we will elucidate the dynamic regulatory connections between PARylation and phosphorylation networks upon DNA damage. In particular, we will identify the export motif and the export carrier of MacroD2 and establish the connection between MacroD2 export and the regulation of the DNA damage response.

细胞通过激活重要的信号传导和修复途径对DNA损伤做出快速反应。细胞事件的协调通常涉及通过翻译后修饰调节细胞核和细胞质之间的蛋白质运输。磷酸化和聚ADP核糖基化（PAR化）构成DNA损伤后调节蛋白质功能的主要信号传导途径。值得注意的是，PAR化是在同源重组和非同源末端连接之间选择双链断裂修复的重要调节因子。虽然这种串扰具有临床相关性，但其分子基础知之甚少。MacroD 2是一种新发现的能够完全逆转蛋白质PAR化的末端ADP-核糖水解酶，是磷酸化和PAR化之间相互作用的重要调节因子。MacroD 2在PAR化后迅速募集到损伤位点，并从蛋白质中去除末端ADP-核糖单元，但响应于DNA损伤反应（DDR）激酶（PIKK）的激活而从细胞核输出。使用活细胞成像，生化分析和高含量的siRNA筛选相结合，拟议的项目将确定这种新的DNA损伤诱导的输出机制的分子基础和调控。此外，我们将阐明PAR化和磷酸化网络之间的动态调节连接DNA损伤。特别是，我们将确定MacroD 2的输出基序和输出载体，并建立MacroD 2输出与DNA损伤反应调控之间的联系。