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Updated: Sep 20, 2025
Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions
Published on: June 7, 2020
Proteomic compensation by paralogs preserves protein interaction networks after gene loss in cancer
Anjan Venkatesh1,2,3, Niall Quinn2,3, Swathi Ramachandra Upadhya1,3
1Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Abstract:
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.
Insights
Tumor cells maintain protein networks despite genetic changes through paralog compensation. Loss of one gene can increase its paralog
Area of Science:
- Proteomics
- Systems Biology
- Cancer Biology
Background:
- Protein-protein interaction networks are crucial for cellular function.
- Tumor cells exhibit resilience to genetic perturbations within these networks.
- Mechanisms underlying this resilience, particularly regarding paralog tolerance, are not fully understood.
Purpose of the Study:
- To systematically profile the proteomic response to gene loss in tumors and cell lines.
- To elucidate the mechanisms of proteomic compensation and collateral loss.
- To investigate the relationship between network centrality, essential functions, synthetic lethality, and proteomic compensation.
Main Methods:
- Systematic proteomic profiling of tumors and cell lines.
- Analysis of gene loss effects on protein abundance.
- Investigation of protein-protein interaction network properties.
- Correlation analysis with synthetic lethality data.
Main Results:
- Identified widespread proteomic compensation (paralog abundance increase) and collateral loss (paralog abundance decrease) following gene loss.
- Compensation is enriched in paralog pairs central to the protein-protein interaction network.
- Compensation is more likely between synthetic lethal gene pairs.
- Compensation is linked to interaction partners performing essential functions.
Conclusions:
- Proteomic compensation involving paralogs helps stabilize protein-protein interaction networks in tumor cells despite genetic perturbations.
- This compensatory mechanism can lead to tumor cell dependency on specific paralogs for survival.
- These findings highlight potentially targetable vulnerabilities in cancer cells.
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