Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells

Abstract

Aneuploidy, an abnormal chromosome composition, results in a stoichiometric imbalance of protein complexes, which jeopardizes the fitness of aneuploid cells. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, a phenomenon known as dosage compensation. However, the molecular mechanisms involved in dosage compensation in human cells - and whether they can be targeted to selectively kill aneuploid cancer cells - remain unknown. Here, we addressed this question via molecular dissection of multiple diploid vs. aneuploid cell models. Using genomic and functional profiling of a novel isogenic system of RPE1-hTERT cells with various degrees of aneuploidy, we found that aneuploid cells cope with both transcriptional burden and proteotoxic stress. At the mRNA level, aneuploid cells increased RNA synthesis, but concomitantly elevated several RNA degradation pathways, in particular the nonsense-mediated decay (NMD) and the microRNA-mediated mRNA silencing pathways. Consequently, aneuploid cells were more sensitive to the genetic or chemical perturbation of several key components of these RNA degradation pathways. At the protein level, aneuploid cells experienced proteotoxic stress, resulting in reduced translation and increased protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, confirming that both non-transformed and transformed cells alter their RNA and protein metabolism in order to adapt to the aneuploid state. Our results reveal that aneuploid cells are dependent on the over- or under-activation of several nodes along the gene expression process, identifying these pathways as clinically-actionable vulnerabilities of aneuploid cells.

CDC20 determines the sensitivity to spindle assembly checkpoint (SAC) inhibitors

“…Aneuploidy and CIN are associated with cancer progression and drug response. CIN and aneuploidy were previously linked to increased drug resistance to many anticancer drugs (Lee et al, 2011; Replogle et al, 2020; Ippolito et al, 2021; Lukow et al, 2021; Cohen-Sharir et al, 2021), but they can also lead to increased sensitivity to specific therapies, such as SAC inhibition (Cohen-Sharir et al, 2021), KIF18A inhibition (Cohen-Sharir et al, 2021; Marquis et al, 2021), Src1 inhibition (Schukken et al, 2020), IL-6R inhibition (Hong et al, 2022), MAPK signaling inhibition (Zerbib et al, 2023) and proteasome inhibition (Ippolito et al, 2023). Understanding the molecular mechanisms that mediate the associations between CIN/aneuploidy and drug response can guide the development of new therapies and promote our basic understanding of cancer.…”

The molecular basis of cell memory in mammals: The epigenetic cycle

“…This supports that stable binding of TFs to target genomic regions during cell cycle transition can endorse transcriptional memory to proliferating cells. However, the distribution of the pluripotency TFs OCT4 and SOX2 on mitotic chromosomes can vary depending on the experimental conditions used, which probably reflects the difficulty of capturing dynamic interactions between TFs and mitotic chromatin ( 145 , 148 , 153 – 156 ). This new role of TFs as mitotic bookmarks might prompt the conclusion that TFs endorse epigenetic memory to the genome, however their mode of action should not be considered an epigenetic mechanism because (i) it is highly dependent on their sequence-specific binding, and (ii) they constitute at the same time the initial trigger that changes gene expression and the mechanism that facilitates its maintenance.…”

A compendium of Amplification-Related Gain Of Sensitivity (ARGOS) genes in human cancer

“…3a; c ). As gene dosage compensation has previously been shown to primarily occur at the level of protein complexes 5,10,40 , we investigated their functional impact based on complex membership: Prioritizing both by the number of compensated genes within a complex and by their degree of toxicity ( Fig. 3d ), the top 'hits' of this analysis are RBM14 (acting in the HEXIM1-DNA-PK-paraspeckle ribonucleoprotein complex, HDP-RNP; FDR = 0.003 ) and SNRPA (involved in U1A splicing; FDR = 0.025 ).…”

“…To validate these as compensated genes, we examined gene expression and calculated gene compensation scores in isogenic RPE-1 clones with gained chromosomes (either chromosome 7 or a combination of chromosome 7 and 22; or 8, 9 and 18; for 7, 10 and 7 compensated genes Fig. S2e ) 10,37 . We confirmed that the compensated genes residing on the respective gained chromosomes were expressed less than non-compensated genes thereon ( P < 0.05).…”

“…promoter hypermethylation) and post-translational (e.g. buffering copy number imbalances in protein complex members) levels [6][7][8][9][10][11][12] .…”