A central control hub in DNA damage responses: function and regulation of the RBR module

DNA 损伤反应的中央控制中心：RBR 模块的功能和调节

• 批准号: 431823631
• 负责人: Professor Dr. Arp Schnittger
• 金额: --
• 依托单位: Biozentrum Klein Flottbek und Botanischer Garten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/431823631?language=en
• 关键词: central; control; hub; DNA; damage

DNA damage represents a critical threat to every cell in all organisms. Globally, the DNA Damage Response (DDR) consists of a set of tightly regulated events, from sensing of the inflicted damage, activation of a DDR signalling cascade that also blocks cell cycle progression, accumulation of DNA repair factors at the damaged site, to the physical repair of the lesion and/or the replacement of damaged cells. Remarkably, plants can cope with very high concentrations of harmful agents in comparison to animals. Despite this apparent power and their relevance for agriculture under changing environmental conditions, the plant DNA repair pathways are not very well understood. Moreover, the canonical response pathways of yeast and animals appear to be only partially conserved raising the question of how plants can so efficiently repair DNA damage and which regulators are employed in this process. In this context, the preparatory work of both partners has revealed a DDR network relying on the Arabidopsis pRb homolog, called RETINOBLASTOMA RELATED 1 (RBR1). RBR1 appears to function in at least two ways: first, as a transcriptional regulator of DDR genes and second, as a potential assembly factor of repair complexes at the lesion sites. Thus, RBR1 acts as a central control hub in DDR and hence offers a unique starting point to get mechanistic insights into the DDR of plants. Following up on the genome-wide identification of RBR1 binding sites and the proteome-wide protein-protein interaction network of RBR1 under DNA damaging conditions, an aim of this project is to combine the complementary expertise of both partners to understand the molecular mechanism of how targets of RBR1 are controlled upon DNA damage and explore the function of unknown DDR related RBR1 target genes. At the same time, we will investigate how RBR1 itself is regulated upon DNA damage. Since the preparatory work of both partners indicated a prominent role of proteolytic regulation for both the RBR1 functional complex(es) as well as several of its target genes, special emphasis is put on this aspect. To that end, and supported by extensive preparatory data, we follow the hypothesis that the F-box protein FBL17, previously identified in collaborative effort of the two partners, plays a central role in RBR1 homeostasis and might be also involved in selective degradation of RBR1 targets involved in DDR.

DNA损伤对所有生物体中的每个细胞都是一个严重的威胁。在全球范围内，DNA损伤反应（DDR）由一组严格调控的事件组成，从感知所造成的损伤，激活DDR信号级联，也阻断细胞周期进程，DNA修复因子在受损部位的积累，到损伤的物理修复和/或受损细胞的替换。值得注意的是，与动物相比，植物可以科普非常高浓度的有害物质。尽管这种明显的力量和它们在不断变化的环境条件下与农业的相关性，但植物DNA修复途径并没有得到很好的理解。此外，酵母和动物的典型反应途径似乎只是部分保守的，这就提出了一个问题，即植物如何能够如此有效地修复DNA损伤，以及在这一过程中采用了哪些调节剂。在这种情况下，两个合作伙伴的准备工作揭示了依赖于拟南芥pRb同源物的DDR网络，称为视网膜母细胞瘤相关1（RBR 1）。RBR 1似乎至少以两种方式发挥作用：第一，作为DDR基因的转录调节因子，第二，作为损伤部位修复复合物的潜在组装因子。因此，RBR 1作为DDR中的中央控制中心，因此提供了一个独特的起点，以获得对工厂DDR的机械见解。本项目的目标是通过联合收割机的互补性研究，进一步了解DNA损伤条件下RBR 1结合位点的全基因组识别和RBR 1蛋白质组相互作用网络，了解RBR 1靶基因在DNA损伤后的分子调控机制，并探索未知的DDR相关RBR 1靶基因的功能。同时，我们将研究RBR 1本身如何在DNA损伤后进行调节。由于两个合作伙伴的准备工作表明蛋白水解调节的RBR 1功能复合物（ES）以及它的几个靶基因的突出作用，特别强调这方面。为此，并支持广泛的准备数据，我们遵循的假设，即F盒蛋白FBL 17，以前确定的合作努力的两个合作伙伴，发挥核心作用的RBR 1稳态，也可能参与选择性降解的RBR 1目标参与DDR。