Disrupting DNA G-quadruplex secondary structures to revert premature ageing

衰老的根本原因仍然是生物学的核心奥秘之一。最近对几种不同生物模型的研究表明，不仅衰老的速度可以被环境和遗传因素所改变，而且衰老时钟可以被逆转，使衰老的细胞和组织恢复年轻的特征。细胞核中的DNA包装和组织已被证明在衰老和一些加速衰老疾病中发生了显着改变。用小分子配体治疗可以干扰核组织，恢复患者来源细胞的过早衰老。DNA非规范结构，特别是DNA g -四重结构，也被证明在一些加速衰老综合征的DNA包装中起作用。事实上，特定g -四重体解绕蛋白的突变和这些DNA结构的积累已被证明是加速衰老综合征（如柯凯因综合征）的潜在原因。以DNA及其结构特征为目标，进一步加深我们对基本衰老生物学的理解，并探索罕见的加速衰老疾病的治疗干预潜力，是一个尚未被探索的机会，需要研究。在这里，我将利用一系列化学生物学工具来研究DNA g -四重体结构在衰老生物学中的基本作用，并通过开发靶向和破坏这些结构的小分子来探索罕见加速衰老综合征的治疗干预潜力。具体来说，我将把我在DNA g -四重体靶向和全基因组定位方面的经验与伦敦帝国理工学院化学系与Vilar博士合作开发的g -四重体选择性活细胞成像方法结合起来。我打算解决这些具体问题：1)加速衰老疾病中g -四重体在全基因组范围内的普遍变化是什么？它们的形成如何影响DNA包装？2)靶向和破坏通过衰老积累的g -四联体能否通过恢复正确的DNA包装来恢复衰老表型？3)在衰老过程中导致g -四重体形成的活细胞中，与DNA转录和复制相关的动力学是什么？解决这些问题将进一步加深我们对DNA二级结构形成与导致衰老的基因调控错误之间的因果关系的理解。这将为开发新的治疗药物铺平道路，最终将增加健康寿命并治疗罕见的加速衰老综合征。

The underlying cause of aging remains one of the central mysteries of biology. Recent studies in several different biological models suggest that not only can the rate of aging be modified by environmental and genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues.DNA packaging and organisation in the cell nucleus has been shown to be significantly altered thorough ageing and some accelerating ageing disorders. Treatment with small molecule ligands can interfere with nuclear organisation and revert premature ageing sings in patient-derived cells. DNA non-canonical structures, in particular DNA G-quadruplex structures, have also shown to play a role in DNA packaging in some accelerating ageing syndromes. Indeed, mutation of specific G-quadruplex unwinding proteins and accumulation of these DNA structures have been shown to be the underlying cause of accelerating ageing syndromes, such as Cockayne syndromes. Targeting DNA and its structural feature to both further our understating in fundamental ageing biology and explore potential for therapeutic intervention of rare accelerating ageing disorders, is an unexplored opportunity that needs to be investigated.Here, I will exploit a range of chemical biology tools to both investigate the fundamental role of DNA G-quadruplex structures in ageing biology, and explore the potential for therapeutic intervention of rare accelerating ageing syndromes by developing small molecules to target and disrupt these structures. Specifically, I will combine my experience with DNA G-quadruplex targeting and genome-wide mapping with a G-quadruplex selective live-cell imaging methodology that has been developed at the chemistry department of Imperial College London in collaboration with Dr. Vilar. I intend to address these specific questions:1) What are the global changes in G-quadruplex prevalence genome-wide in accelerating ageing disorders and how is DNA packaging affected by their formation? 2) Can targeting and disrupting the G-quadruplexes that accumulate via ageing be used to revert the ageing phenotypes by restoring correct DNA packaging?3) What are the dynamics in living cells, with respect to transcription and replication of DNA, that cause G-quadruplex formation thorough ageing?Addressing these questions will further our understanding of the cause and effect relationship between DNA secondary structure formation and gene mis-regulation that cause ageing. This will pave the way towards the development of novel therapeutic agents which will ultimately increase health-span and treat rare accelerating ageing syndromes.