Venkatesh Anjan, Quinn Niall, Upadhya Swathi Ramachandra, De Kegel Barbara, Bolado Carrancio Alfonso, Lefeivre Thomas, Dennler Olivier, Wynne Kieran, von Kriegsheim Alexander, Ryan Colm J
Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Systems Biology Ireland, University College Dublin, Dublin, Ireland.
Mol Syst Biol. 2025 May 28. doi: 10.1038/s44320-025-00122-4.
Proteins operate within dense interconnected networks, with interactions necessary both for stabilising proteins and enabling them to execute their molecular functions. Remarkably, protein-protein interaction networks operating within tumour cells continue to function despite widespread genetic perturbations. Previous work has demonstrated that tumour cells tolerate perturbations of paralogs better than perturbations of singleton genes, but the underlying mechanisms remain poorly understood. Here, we systematically profile the proteomic response of tumours and cell lines to gene loss. We find many examples of proteomic compensation, where loss of one gene causes increased abundance of a paralog, and collateral loss, where gene loss causes reduced paralog abundance. Compensation is enriched among paralog pairs that are central in the protein-protein interaction network and whose interaction partners perform essential functions. Compensation is also significantly more likely to be observed between synthetic lethal pairs. Our results support a model whereby loss of one gene results in increased protein abundance of its paralog, stabilising the protein-protein interaction network. Consequently, tumour cells may become dependent on the paralog for survival, creating potentially targetable vulnerabilities.
蛋白质在密集的相互连接网络中发挥作用，这些相互作用对于稳定蛋白质以及使其能够执行分子功能都是必需的。值得注意的是，尽管存在广泛的基因扰动，肿瘤细胞内的蛋白质 - 蛋白质相互作用网络仍在继续发挥作用。先前的研究表明，肿瘤细胞对旁系同源基因扰动的耐受性优于对单拷贝基因的扰动，但其潜在机制仍知之甚少。在这里，我们系统地分析了肿瘤和细胞系对基因缺失的蛋白质组学反应。我们发现了许多蛋白质组学补偿的例子，即一个基因的缺失会导致旁系同源基因丰度增加，以及间接损失的例子，即基因缺失会导致旁系同源基因丰度降低。补偿在蛋白质 - 蛋白质相互作用网络中处于中心位置且其相互作用伙伴执行基本功能的旁系同源基因对中更为丰富。在合成致死对之间也更有可能观察到补偿。我们的结果支持一种模型，即一个基因的缺失会导致其旁系同源基因的蛋白质丰度增加，从而稳定蛋白质 - 蛋白质相互作用网络。因此，肿瘤细胞可能会依赖旁系同源基因来生存，从而产生潜在的可靶向弱点。
