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，当细胞分裂时，它会通过称为细胞分裂的过程创建自身的完美副本，包括其基因组副本，该过程将细胞及其内容物物理分离成两半，成为两个新的、基因相同的细胞。这个过程必须精确，因此受到严格控制。细胞确保细胞分裂无错误发生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，以确保不发生错误。两个新基因组的精确分离过程中发生的任何错误都可能导致戏剧性的、潜在致癌的基因突变或细胞死亡。许多不同类型癌症中的一种常见突变发生在 p53 基因中，该基因也被称为“基因组守护者”，因为它对于保护细胞在细胞分裂过程中免受错误非常重要。如果 p53 或与 p53 相关的其他基因发生突变，一些细胞周期检查点将不再起作用，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 突变，细胞周期检查点本应确保 DNA 在分离成两个新细胞之前解开缠结，该检查点将不起作用，因此某些癌细胞不太擅长解开 DNA。 癌症细胞已经进化出一个备用途径来处理这个问题。他们被迫触发一组“故障安全”蛋白质来完成解开 DNA 的工作，以便每个新细胞获得相同的基因组副本。我们现在需要新的知识来理解为什么 p53 突变会导致 DNA 解缠结监视检查点的丢失，以及参与备份途径的确切故障保护蛋白是什么。一旦我们了解到这一点，我们希望将这一发现转化为一种新的癌症疗法。我们发现了一种使用针对这些故障安全蛋白的药物来杀死癌细胞的新方法。由于只有癌细胞需要故障安全蛋白，因此这些药物不会影响正常、健康的细胞，这意味着对患者的副作用更少。