Investigating cell cycle vulnerabilities in TP53 mutant cancers

正常情况下，当一个细胞分裂时，它会创造一个完美的自身副本，包括它的基因组副本，这一过程被称为细胞分裂，将细胞及其内容物物理地分成两半，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，以确保没有错误发生。在两个新基因组的精确分离过程中出现的任何错误都可能导致戏剧性的、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基因上，该基因也被称为“基因组守护者”，因为它在细胞分裂过程中保护细胞免受错误的影响非常重要。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突变，细胞周期检查点应该确保DNA在分裂成两个新细胞之前得到解开，但它不起作用，所以一些癌细胞不太擅长解开它们的DNA。癌细胞已经进化出了一种能够处理这种情况的备用途径。它们被迫触发一组“万无一失”的蛋白质来完成解开DNA的工作，这样每个新细胞都能得到相同的基因组拷贝。我们现在需要新的知识来理解为什么p53突变会导致DNA纠错监视检查点的丢失，以及备份途径中涉及的确切的故障安全蛋白是什么。一旦我们了解到这一点，我们希望将这一发现转化为癌症的新疗法。我们已经发现了一种杀死癌细胞的新方法，使用靶向这些失效保护蛋白的药物。由于只有癌细胞才需要失效保护蛋白，因此这些药物将不影响正常、健康的细胞，这意味着对患者的副作用更小。

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.