Amyotrophic Lateral Sclerosis and the DNA Damage Response

肌萎缩侧索硬化症和 DNA 损伤反应

• 批准号: MR/K01854X/1
• 负责人: Keith Caldecott
• 金额: $ 45.86万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK01854X%2F1
• 关键词: Amyotrophic; Lateral; Sclerosis; DNA; Damage

Amyotrophic Lateral Sclerosis (ALS) is caused by premature/accelerated degeneration of motor neurones. Whereas some cases of ALS are sporadic and of unknown molecular cause, others are due to hereditary dominant mutations in one of approximately eight genes. It has emerged recently that several of the proteins encoded by these genes are involved in regulating the production of messenger RNA (mRNA); a process known as transcription by which genes are copied into mRNA during gene expression. Two of these proteins are Fused-in-Sarcoma/Translocated-in-Sarcoma (FUS/TLS) and TAR DNA-binding protein 43 (TDP-43). The association of FUS/TLS and TDP-43 with ALS suggests that, in some cases of this disease, neuronal cell death may involve loss-of-function defects in RNA processing. However, the putative roles fulfilled by RNA processing that prevent ALS are unclear. We now present a novel hypothesis and supporting preliminary evidence for how RNA processing might prevent ALS. We show that FUS/TLS and TDP-43 are redistributed in response to DNA damage, with FUS rapidly accumulating at sites of DNA damage and TDP-43 rapidly expelled. We show that this redistribution of FUS/TLS and TDP-43 is an active process that is regulated by proteins with established roles in DNA damage signaling, supporting the idea that RNA processing is a bona fide component of the cellular DNA damage response. Based on these observations, we propose that RNA processing by FUS/TLS and TDP-43 is required to ensure that transcription is properly managed and controlled in the presence of DNA lesions, and that mutation of these and likely other proteins involved in RNA processing results in dysfunctional gene expression and neuronal cell death. In this application, we plan to address this hypothesis directly, using a combination of molecular and cellular approaches. To do this we have divided the proposed work into three specific objectives. We will, 1. Identify the mechanism/s by which FUS/TLS and TDP-43 are redistributed in response to DNA damage. 2. Address the role of FUS/TLS and TDP-43 in DNA damage signaling and/or repair at sites of DNA damage, and how these proteins regulate transcription in the presence of DNA lesions that block this process. 3. Examine the importance of FUS/TLS and TDP-43 for cellular resistance to DNA damage, including motor neurons, and identify additional components of RNA processing during the DNA damage response.

肌萎缩侧索硬化症（ALS）是由运动神经元的过早/加速变性引起的。虽然有些ALS病例是散发性的，分子原因不明，但其他病例是由于大约八个基因中的一个遗传显性突变。最近发现，这些基因编码的几种蛋白质参与调节信使RNA（mRNA）的产生;这一过程称为转录，基因在基因表达过程中复制成mRNA。这些蛋白质中的两种是肉瘤融合/肉瘤易位（FUS/TLS）和TAR DNA结合蛋白43（TDP-43）。FUS/TLS和TDP-43与ALS的关联表明，在这种疾病的某些情况下，神经元细胞死亡可能涉及RNA加工中的功能缺失缺陷。然而，RNA加工在预防ALS中的假定作用尚不清楚。我们现在提出了一个新的假设，并支持RNA加工如何预防ALS的初步证据。我们发现，FUS/TLS和TDP-43在DNA损伤后重新分布，FUS在DNA损伤部位迅速积累，TDP-43迅速排出。我们表明，FUS/TLS和TDP-43的这种重新分布是一个活跃的过程，受在DNA损伤信号传导中具有既定作用的蛋白质的调节，支持RNA加工是细胞DNA损伤反应的真正组成部分的观点。基于这些观察结果，我们提出，需要FUS/TLS和TDP-43进行RNA加工，以确保在存在DNA损伤的情况下转录得到适当的管理和控制，并且这些和可能参与RNA加工的其他蛋白质的突变导致功能失调的基因表达和神经元细胞死亡。在本申请中，我们计划使用分子和细胞方法的组合直接解决这一假设。为此，我们将拟议的工作分为三个具体目标。我们会的，1。确定FUS/TLS和TDP-43响应DNA损伤而重新分布的机制。2.解决FUS/TLS和TDP-43在DNA损伤信号传导和/或DNA损伤位点修复中的作用，以及这些蛋白质如何在存在DNA损伤的情况下调节转录，从而阻止这一过程。3.研究FUS/TLS和TDP-43对细胞抵抗DNA损伤的重要性，包括运动神经元，并确定DNA损伤反应期间RNA加工的其他成分。

项目成果

PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage.

• DOI: 10.1093/nar/gkt835
• 发表时间: 2014-01
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Rulten SL;Rotheray A;Green RL;Grundy GJ;Moore DA;Gómez-Herreros F;Hafezparast M;Caldecott KW
• 通讯作者: Caldecott KW