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.

正常情况下，当细胞分裂时，它会通过一个称为细胞分裂的过程创建一个完美的自身拷贝，包括其基因组拷贝，该过程将细胞及其内容物物理分离成两半，成为两个新的，遗传上相同的细胞。这个过程必须精确，因此受到严格控制。细胞确保细胞分裂没有错误的一种方法是检查点的存在-这些是细胞在分裂周期中暂停的地方，以确保没有错误。在两个新基因组的精确分离中发生的任何错误都可能导致戏剧性的和潜在的致癌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基因中，也被称为“基因组的守护者”，因为它在保护细胞免受细胞分裂过程中的错误方面非常重要。如果p53或其他与p53相关的基因发生突变，一些细胞周期检查点不再起作用，这意味着细胞现在可以继续分裂，即使它有错误。我们发现，如果p53发生突变，细胞周期检查点将无法确保DNA在分离成两个新细胞之前解开，因此一些癌细胞不擅长解开它们的DNA。癌细胞已经进化到有一个备用途径来处理这个问题。它们被迫触发一组“故障安全”的蛋白质来完成解开DNA的工作，这样每个新细胞都能获得相同的基因组拷贝。我们现在需要新的知识来理解为什么p53突变会导致DNA解缠结监测检查点的丢失，以及备份途径中涉及的确切故障安全蛋白质是什么。一旦我们了解了这一点，我们希望将这一发现转化为癌症的新疗法。我们已经发现了一种新的方法来杀死癌细胞，使用靶向这些故障安全蛋白质的药物。由于故障安全蛋白质只需要癌细胞，因此这些药物将单独离开正常，健康的细胞，这意味着对患者的副作用较少。