文章：

通过蛋白质-蛋白质相互作用解码癌症基因组的功能影响

Decoding the functional impact of the cancer genome through protein–protein interactions

原文发布日期：2025-01-14

DOI: 10-1038-s41568-024-00784-6

类型: Review Article

开放获取: 否

英文摘要：

Acquisition of genomic mutations enables cancer cells to gain fitness advantages under selective pressure and, ultimately, leads to oncogenic transformation. Interestingly, driver mutations, even within the same gene, can yield distinct phenotypes and clinical outcomes, necessitating a mutation-focused approach. Conversely, cellular functions are governed by molecular machines and signalling networks that are mostly controlled by protein–protein interactions (PPIs). The functional impact of individual genomic alterations could be transmitted through regulated nodes and hubs of PPIs. Oncogenic mutations may lead to modified residues of proteins, enabling interactions with other proteins that the wild-type protein does not typically interact with, or preventing interactions with proteins that the wild-type protein usually interacts with. This can result in the rewiring of molecular signalling cascades and the acquisition of an oncogenic phenotype. Here, we review the altered PPIs driven by oncogenic mutations, discuss technologies for monitoring PPIs and provide a functional analysis of mutation-directed PPIs. These driver mutation-enabled PPIs and mutation-perturbed PPIs present a new paradigm for the development of tumour-specific therapeutics. The intersection of cancer variants and altered PPI interfaces represents a new frontier for understanding oncogenic rewiring and developing tumour-selective therapeutic strategies.

摘要翻译： 

基因组突变的获得使癌细胞能够在选择压力下获得适应性优势，并最终导致癌变。有趣的是，驱动突变即使在同一基因内也可能产生不同的表型和临床结果，因此需要采用以突变为中心的研究方法。相反，细胞功能由分子机器和信号网络控制，这些网络主要受蛋白质-蛋白质相互作用（PPIs）调控。个体基因组变异的功能影响可能通过PPIs的调控节点和枢纽进行传递。致癌突变可能导致蛋白质残基修饰，使其能够与野生型蛋白通常不相互作用的其他蛋白质结合，或阻止与野生型蛋白通常相互作用的蛋白质结合。这可能导致分子信号级联的重连和致癌表型的获得。在此，我们回顾了由致癌突变驱动的PPIs改变，讨论了监测PPIs的技术，并对突变导向的PPIs进行了功能分析。这些由驱动突变实现的PPIs和突变干扰的PPIs为开发肿瘤特异性疗法提供了新范式。癌症变异与改变的PPI界面的交叉领域，代表了理解致癌重连和开发肿瘤选择性治疗策略的新前沿。

原文链接：

Decoding the functional impact of the cancer genome through protein–protein interactions