Regulation of protein complex partners as a compensatory mechanism in aneuploid tumors

Abstract

Aneuploidy, a state of chromosome imbalance, is a hallmark of human tumors, but its role in cancer still remains to be fully elucidated. To understand the consequences of whole-chromosome-level aneuploidies on the proteome, we integrated aneuploidy, transcriptomic and proteomic data from hundreds of TCGA/CPTAC tumor samples. We found a surprisingly large number of expression changes happened on other, non-aneuploid chromosomes. Moreover, we identified an association between those changes and co-complex members of proteins from aneuploid chromosomes. This co-abundance association is tightly regulated for aggregation-prone aneuploid proteins and those involved in a smaller number of complexes. On the other hand, we observe that complexes of the cellular core machinery are under functional selection to maintain their stoichiometric balance in aneuploid tumors. Ultimately, we provide evidence that those compensatory and functional maintenance mechanisms are established through post-translational control and that the degree of success of a tumor to deal with aneuploidy-induced stoichiometric imbalance impacts the activation of cellular protein degradation programs and patient survival.

Extensive protein dosage compensation in aneuploid human cancers

“…This trend is exemplified by ribosomal complex proteins ( Stingele et al 2012 ; Dephoure et al 2014 ), which showed highly significant dosage compensation. A recent study showed that protein complex subunits located on nonaneuploid chromosomes tend to co-regulate with their co-complex partners on aneuploid chromosomes in human tumor samples ( Senger et al 2022 ). We discovered that protein complex subunits were also buffered upon chromosome arm loss.…”

Gene dosage compensation: Origins, criteria to identify compensated genes, and mechanisms including sensor loops as an emerging systems‐level property in cancer

“…Mostly protein level compensation. RNA-level compensation in certain tumor types RNA-level compensation for non-complex genes RNA-protein correlation informs protein-level regulation [43] DNA-RNA correlation informs RNAlevel regulation [43] Protein complexes Genes that code for protein complexes Accelerated breakdown of nonassembled subunits [78,79] Protein degradation by ubiquitinproteasome system [78,80,81] Acetylation of the N-terminal amino acid by N-acetyltransferases (NAT) [79,81,82] Co-deregulation of protein complex partners [83] (Continues) addition, when combined with criteria such as the formation of protein complexes, only 70% of NED proteins form those complexes. Therefore, a precise definition of gene dosage compensation is difficult to achieve, especially because the threshold of the gene expression scaling as a function of copy number could be different for each gene and probably also depends on the cellular context.…”

“…43 A characterization of the transcriptome and proteome in aneuploid human cancers showed that 47%-63% of the genes located in aneuploid chromosomes evidence changes in expression at the transcriptome level, in contrast to only 24%-33% at the proteome level. 83 However, the degree of expression changes induced by aneuploidy varies depending on multiple factors, among them the cellular environment. 16 For instance, Senger et al found that genes on other chromosomes show a surprising degree of differential expression.…”

“…When performing the comparison of the transcriptome and proteome data, it was observed that the proteomic changes of the aneuploid chromosomes could be explained mainly by the differential expression of their corresponding genes in the transcriptome, even so, these observations are not concordant for the proteomic changes of non-aneuploid chromosomes. 83 Moreover, Gonçalves et al performed an analysis of transcriptomic and proteomic datasets of 282 breast, ovarian, and colorectal tumor samples available in the CPTAC and TCGA consortia, finding that CNVs are buffered by post-transcriptional regulation at the protein level only in 23%-33% of the proteins that are part of protein complexes, indicating that other mechanisms should be at work. 100 The studies described above indicate the existence of different contributions of the regulatory levels of gene dosage compensation, where the RNA-level regulation predominates in genes within aneuploid chromosomes, while for other chromosomes translational or post-translational control has a comparatively greater importance.…”

“…100 The studies described above indicate the existence of different contributions of the regulatory levels of gene dosage compensation, where the RNA-level regulation predominates in genes within aneuploid chromosomes, while for other chromosomes translational or post-translational control has a comparatively greater importance. 83 We detail below though mechanisms of transcriptional or post-transcriptional control at the RNA level that have been proposed to play a role in gene dosage compensation.…”