The shielding role of the nuclear periphery against the genetic and non-genetic consequences of DNA damage (ChromoSENSOR)

核外围对 DNA 损伤的遗传和非遗传后果的屏蔽作用 (ChromoSENSOR)

• 批准号: EP/Y027124/1
• 负责人: Evi Soutoglou
• 金额: $ 233.84万
• 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: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY027124%2F1
• 关键词: shielding; role; nuclear; periphery; against

A key feature of the mammalian nucleus is the non-random arrangement of the genome within the nuclear space, which is linked to how cells cope with DNA damage. Tethering heterochromatin to the nuclear lamina to form the Lamina Associated domains (LADs), protects repetitive DNA from illegitimate recombination and enhances the ability of the nucleus to resist mechanical forces, which can lead to DNA damage. In addition to jeopardizing genomic integrity, DNA damage has non genetic consequences. It affects the integrity of the nuclear lamina, leads to changes in the epigenome and alters the propensity of DNA to associate with the nuclear periphery. All these changes, need to be restored to maintain cell fitness. The mechanisms by which non-random genome organization, and particularly LADs, protect cells against the genetic and non-genetic consequences of DNA damage are unknown.We will use innovative protein-targeting strategies to induce LAD-specific DNA breaks, to unravel how LADs control DNA repair pathway choice to supress recombination between repeats and whether compromising LAD integrity correlates with structural variations in cancer genomes. We will determine whether the epigenome is restored after DNA repair and whether LAD-position is inherently altered, impacting cell identity. Finally, using precise mechanical manipulation of the nucleus, we will investigate how the nuclear periphery protects the genome from mechanical stress-induced DNA damage. This proposal will uncover the mechanisms that preserve LAD genome and epigenome integrity and will have a significant impact on our understanding of how cell fitness after DNA damage is enforced. We will also gain insight into the complex relationship between chromatin mechanics and DNA damage and reveal the changes that the nuclear periphery undergoes to protect genome integrity. This knowledge will be essential to determine how we can engineer chromatin state to exploit it for cancer treatment.

哺乳动物细胞核的一个关键特征是基因组在核空间内的非随机排列，这与细胞如何应对 DNA 损伤有关。将异染色质束缚在核纤层上形成核纤层相关结构域 (LAD)，可保护重复 DNA 免遭非法重组，并增强细胞核抵抗可能导致 DNA 损伤的机械力的能力。 DNA 损伤除了危害基因组完整性外，还会产生非遗传后果。它影响核纤层的完整性，导致表观基因组的变化，并改变 DNA 与核外围结合的倾向。所有这些变化都需要恢复以维持细胞健康。非随机基因组组织（尤其是 LAD）保护细胞免受 DNA 损伤的遗传和非遗传后果的机制尚不清楚。我们将使用创新的蛋白质靶向策略来诱导 LAD 特异性 DNA 断裂，以揭示 LAD 是如何控制 DNA 修复途径选择以抑制重复之间的重组，以及损害 LAD 完整性是否与癌症基因组的结构变异相关。我们将确定 DNA 修复后表观基因组是否恢复，以及 LAD 位置是否发生本质改变，从而影响细胞身份。最后，通过对细胞核进行精确的机械操作，我们将研究细胞核外围如何保护基因组免受机械应力引起的 DNA 损伤。该提案将揭示保护 LAD 基因组和表观基因组完整性的机制，并将对我们理解 DNA 损伤后细胞适应性如何实施产生重大影响。我们还将深入了解染色质力学与 DNA 损伤之间的复杂关系，并揭示核外围为保护基因组完整性而发生的变化。这些知识对于确定我们如何设计染色质状态以利用它进行癌症治疗至关重要。