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Paralog protein compensation preserves protein-protein interaction networks following gene loss cancer

ABSTRACT: Abstract Proteins operate within dense interconnected networks, where interactions are necessary both for stabilising proteins and enabling them to execute their molecular functions. Remarkably, the 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 mechanistic means by which paralogs tolerate perturbation remain poorly characterised. Here we systematically profile the proteomic response of tumours and tumour cell lines to gene loss. We find many examples of both active compensation, where deletion of one paralog results in increased abundance of another, and collateral loss, where deletion of one paralog results in reduced abundance of another. Active compensation is enriched among sequence-similar paralog pairs that have high protein-protein interaction degree and that are widely conserved across evolution. Active compensation is also significantly more likely to be observed for gene pairs with a known synthetic lethal relationship. Compensating paralogs have more ubiquitination sites, suggesting a role for post-transcriptional control by protein degradation. 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 become dependent on the paralog for survival, creating potentially targetable vulnerabilities.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Myeloid Cell

DISEASE(S): Chronic Myeloid Leukemia

SUBMITTER: Kieran Wynne

LAB HEAD: Dr Colm Ryan

PROVIDER: PXD055643 | Pride | 2025-05-07

REPOSITORIES: Pride

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Project description:To determine whether DGCR8 is required for maturation of all miRNAs, we performed miRNA microarray analysis. Using RNA from wild-type ES cells as our reference sample, we observed a global loss of miRNAs in DGCR8 knockout cells, but normal levels of expression in DGCR8 heterozygous cells. The similarity in expression levels between wild-type and heterozygous cells suggests that DGCR8 is not limiting in the maintenance of steady-state levels of miRNAs in ES cells. Of the eighty-nine miRNA array probes that showed significant signals with wild-type RNA, eighty-two were drastically reduced in the DGCR8 knockout cells. The remaining seven were not significantly altered in the DGCR8 knockout cells, but at least four of these seven miRNAs appear to be due to unavoidable contamination with RNA from the mouse embryonic fibroblast (MEF) feeder cells used for ES cell culture prior to the isolation of RNA. These miRNAs were highly expressed in the MEFs and decreased when the ES cells were temporarily passaged on gelatin-coated plates without feeders. The remaining three showed similar levels of expression in the heterozygous, knockout and MEF feeder cells. Therefore, these signals may be small RNAs that are not processed with the help of the microprocessor complex. Alternatively, these signals may result from unavoidable degradation products within the purified small RNA population. In either case, our results show that DGCR8 is broadly required for miRNA processing with little evidence for redundancy or bypass mechanisms. Keywords: cell type comparison, genetic modification MicroRNAs extracted from wild-type, DGCR8 heterozygous knockout and DGCR8 homozygous knockout were analyzed by microarray. In each array, wild-type samples serve as reference. Ratios were normalized based on positive control RNAs on the array. To determine if some of signals appeared in DGCR8 knockout ES cells are due to mice embryonic fibroblast (MEF) feeder cell contamination (this is unavoidable because these ES cells were grown on MEFs and passaged off MEF before RNA extraction). Two independent DGCR8 knockout ES cell lines were analyzed. For each cell line, array hybridization was done in duplicates. For DGCR8 heterozygous knockout ES cells, two independent batches of RNA samples were prepared and analyzed.

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Paralog protein compensation preserves protein-protein interaction networks following gene loss cancer

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