Investigating cell cycle vulnerabilities in TP53 mutant cancers

研究 TP53 突变癌症的细胞周期脆弱性

• 批准号: MR/Y01264X/1
• 负责人: Tanya Soliman
• 金额: $ 93.83万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY01264X%2F1
• 关键词: Investigating; cell; cycle; vulnerabilities; TP53

Normally when a cell divides it creates a perfect copy of itself, including its copy of the genome through a process called cell division that physically separates the cell and its contents into two halves that become two new, genetically identical cells. This process must be precise and so is stringently controlled. One way the cell makes sure that cell division occurs without errors is the presence of checkpoints - these are places that the cell pauses in the division cycle to ensure that no mistakes have been made. Any mistakes that occur in the precise separation of the two new genomes can lead to dramatic and potentially cancer-causing genetic mutations, or cell death. One common mutation in many different types of cancer occurs in the gene for p53, also known as 'the guardian of the genome' because it is so important in protecting the cell from mistakes during cell division. If p53, or other genes that are associated with p53 to do its job are mutated, some cell cycle checkpoints no longer work, meaning that the cell can now continue dividing even though it has mistakes. We discovered that a cell cycle checkpoint that is supposed to make sure that the DNA gets untangled before it separates into the two new cells doesn't function if p53 is mutated, so some cancer cells aren't very good at untangling their DNA.Cancer cells have evolved to have a back-up pathway to be able to deal with this. They are forced to trigger a 'failsafe' set of proteins to get the job of untangling the DNA done so that each new cell gets an equal copy of the genome. We now require new knowledge in order to understand why mutation of p53 leads to loss of the DNA detangling surveillance checkpoint and what are the exact failsafe proteins involved in the back-up pathway. Once we learn this we want to translate this finding into a new therapy for cancer. We have discovered a new way to kill cancer cells using drugs that target these failsafe proteins. Since the failsafe proteins are only needed by cancer cells, these drugs will therefore leave the normal, healthy cells alone, meaning less side effects for the patients.

通常，当一个细胞划分时，它会创建自身的完美副本，包括通过称为细胞分裂的过程，将细胞及其内容物理分为两个半半，它们变成两个新的，遗传上相同的细胞。此过程必须精确，因此受到严格控制。细胞确保细胞分裂不会出错的一种方式是检查点的存在 - 这些是细胞在分裂周期中暂停以确保没有犯错误的地方。在两个新基因组的精确分离中出现的任何错误都会导致戏剧性的，潜在的引起癌症的基因突变或细胞死亡。在许多不同类型的癌症中，一种常见的突变发生在p53的基因中，也称为“基因组的监护人”，因为它在保护细胞免受细胞分裂过程中的错误中非常重要。如果p53或与p53相关的其他基因被突变，则某些细胞周期检查点不再起作用，这意味着即使存在错误，细胞现在也可以继续分裂。我们发现，一个细胞周期检查点应该确保DNA在分离为两个新细胞之前没有弄脏的DNA在p53被突变之前不起作用，因此某些癌细胞不太擅长解开其DNA。癌细胞已经演变为具有备用途径以能够解决此问题。他们被迫触发一组“故障保护”蛋白，以使DNA完成DNA的工作，以使每个新细胞都获得基因组的平等副本。现在，我们需要新的知识，以了解为什么p53突变会导致DNA缠结监视检查点的丢失，以及备用途径中涉及的确切失败保护蛋白是什么。一旦我们得知这一点，我们就希望将此发现转化为癌症的新疗法。我们发现了一种使用针对这些失败蛋白的药物杀死癌细胞的新方法。由于癌细胞仅需要故障保护蛋白，因此这些药物将使正常的健康细胞单独留下，这意味着对患者的副作用较小。