Discovering how DNA replication errors cause cancer chromosomal instability

发现 DNA 复制错误如何导致癌症染色体不稳定

• 批准号: 2725953
• 金额: --
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2725953
• 关键词: Discovering; how; DNA; replication; errors

AIM: To employ a novel set of state-of-the-art DNA sequencing technologies (including single cell, and single molecule approaches) to dissect the precise impact on the genome of specific deregulated DNA damage repair processes.Rationale:Replication stress is a known driver of human pathologies including aging and cancer, but exact cellular mechanisms involved remain unclear and targeting replication stress therapeutically is still a challenge. Cancer carries a higher intrinsic level of RS compared to normal cells. This increase can theoretically be exploited, however this approach is subject to attaining a precise threshold to avoid toxicity to normal cells. Therefore, to increase specificity for cancer-specific cell killing we are searching for specific mechanistic differences between cancer and normal cells in how they tolerate or repair replication stress and the ensuing chromosomal instability. Various DNA repair pathways exist to deal with, or bypass RS. However the relative use of these in cancer cells which often carry mutations in these pathways is not known. We will determine the genetic signature of specific defects in RS repair in cancer by using a combination of single cell CNA analysis, and newly developed single molecule experiments (targeted long-read sequencing).

目的：采用一套新的国家的最先进的DNA测序技术（包括单细胞，单分子的方法），解剖的精确影响基因组的特定失调DNA损伤修复processes.Rationale：复制压力是一个已知的驱动程序的人类病理学，包括老化和癌症，但确切的细胞机制仍不清楚，靶向复制压力治疗仍然是一个挑战。与正常细胞相比，癌症携带更高的内在RS水平。理论上可以利用这种增加，但是这种方法需要达到精确的阈值，以避免对正常细胞的毒性。因此，为了增加癌症特异性细胞杀伤的特异性，我们正在寻找癌症和正常细胞之间在如何耐受或修复复制应激和随后的染色体不稳定性方面的特定机制差异。存在各种DNA修复途径来处理或绕过RS。然而，这些在癌细胞中的相对使用通常在这些途径中携带突变尚不清楚。我们将通过使用单细胞CNA分析和新开发的单分子实验（靶向长读序测序）的组合来确定癌症中RS修复中特定缺陷的遗传特征。