Systems approaches identify the consequences of monosomy in somatic human cells

Chunduri, Narendra Kumar; Menges, Paul; Gotsmann, Vincent Leon; Zhang, Xiaoxiao; Mardin, Balca R.; Buccitelli, Christopher; Korbel, Jan O.; Willmund, Felix; Kschischo, Maik; Raeschle, Markus; Storchová, Zuzana

doi:10.1101/2021.02.22.432226

Cited by 9 publications

(12 citation statements)

References 64 publications

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“…Interestingly, the existence of protein-level compensation and its higher degree for protein complex genes were true not only for DNA gains, but also for DNA losses. Consistent with our findings, a recent study reported protein-level compensation after chromosome loss (Chunduri et al, 2021) although in this study no significant difference was reported between complex and non-complex genes, perhaps due to the limited number of genes on the lost chromosomes. The protein compensation for complex genes of DNA gains is thought to occur through protein degradation of the overabundant subunits (McShane et al, 2016).…”

Section: Discussionsupporting

confidence: 91%

Proteogenomic analysis of aneuploidy reveals divergent types of gene expression regulation across cellular pathways

Davoli

Pan

Zhao

et al. 2021

Preprint

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How cells control gene expression is a fundamental question. The relative contribution of protein-level and transcript-level regulation to this process remains unclear. Here we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By revealing how cells regulate transcript and protein abundances of SCNA genes, we provide insights into the rules of gene regulation. While gene compensation mainly occurs at the protein level across tumor types, genes gained or lost show surprisingly low protein compensation in lung and high RNA compensation in colon cancer. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong transcript-level regulation. Exceptions are plasma membrane protein complexes showing a very low protein-level regulation. Strikingly, we find a strong negative association between the degree of transcript-level and protein-level regulation across genes and pathways. Moreover, genes participating in the same pathway show similar degree of transcript- and protein-level regulation. Pathways including translation, splicing and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger transcript-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve a predominant mechanism of gene regulation, possibly due to energetic constraints.

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Section: Discussionsupporting

confidence: 91%

Proteogenomic analysis of aneuploidy reveals divergent types of gene expression regulation across cellular pathways

Davoli

Pan

Zhao

et al. 2021

Preprint

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“…Studies performed on single cancer cell lines harboring a few chromosome gains have suggested that human cells similarly overexpress most proteins on gained chromosomes 24,[42][43][44] , with ribosomes and some protein complex subunits exhibiting dosage compensation 24,41,42,45 . Additionally, while chromosome loss events outnumber chromosome gain events in most tumors 46,47 , the cellular effects of chromosome losses in human cancers have not been comprehensively explored 48 .…”

Section: Introductionmentioning

confidence: 99%

Extensive protein dosage compensation in aneuploid human cancers

2021

Preprint

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Aneuploidy is a hallmark of human cancers, but the effects of aneuploidy on protein expression remain poorly understood. To uncover how chromosome copy number changes influence the cancer proteome, we have conducted an analysis of hundreds of human cancer cell lines with matched copy number, RNA expression, and protein expression data. We found that a majority of proteins exhibit dosage compensation and fail to change by the degree expected based on chromosome copy number alone. We uncovered a variety of gene groups that were recurrently buffered upon both chromosome gain and loss, including protein complex subunits and cell cycle genes. Several genetic and biophysical factors were predictive of protein buffering, highlighting complex post-translational regulatory mechanisms that maintain appropriate gene product dosage. Finally, we established that chromosomal aneuploidy has an unexpectedly moderate effect on the expression of oncogenes and tumor suppressors, demonstrating that these key cancer drivers can be subject to dosage compensation as well. In total, our comprehensive analysis of aneuploidy and dosage compensation across cancers will help identify the key driver genes encoded on altered chromosomes and will shed light on the overall consequences of aneuploidy during tumor development.

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“…Although in monosomies this downregulation was previously attributed to haploinsufficiency of ribosomal genes (Chunduri et al, 2021), our data suggest that chromosome gains can possibly also lead to deregulation of these pathways, possibly due to a general aneuploidy-induced stress response (Terhorst et al, 2020). Taken together, although trisomic cells and monosomic cells display different transcriptional responses, the majority of these differences can be explained by their CIN phenotype.…”

Section: Trisomic Clones Show Cin-mediated Differential Expressionmentioning

confidence: 46%

“…The different effects of monosomies and trisomies on CIN have not been studied extensively as most model systems studying the effects of aneuploidy on CIN only focused on chromosome gains (Nicholson et al, 2015;Passerini et al, 2016;Zhu et al, 2012). However, recently it was documented that certain monosomies can trigger a CIN phenotype (Chunduri et al, 2021). There might be several explanations for this apparent discrepancy.…”

Section: Monosomies Are Chromosomally Stablementioning

confidence: 99%

“…Cells deal with the excess of unincorporated proteins by performing dosage compensation (Brennan et al, 2019;Dephoure et al, 2014;Torres et al, 2007Torres et al, , 2010Kojima and Cimini, 2019). This has been shown to occur both in trisomies (Stingele et al, 2012) as well as in monosomies (Chunduri et al, 2021). Although both monosomies and trisomies perform dosage compensation, the critical difference between monosomies and trisomies might be their distinct mechanism for dosage compensation and the associated stress pathways that are induced.…”

Section: Trisomies Cause Cin Levels That Correlate With the Number Of Gained Genesmentioning

confidence: 99%

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Monosomies, trisomies and segmental aneuploidies differentially affect chromosomal stability

Hintzen

Soto

Schubert

et al. 2021

Preprint

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Aneuploidy and chromosomal instability are both commonly found in cancer. Chromosomal instability leads to karyotype heterogeneity in tumors and is associated with therapy resistance, metastasis and poor prognosis. It has been hypothesized that aneuploidy per se is sufficient to drive CIN, however due to limited models and heterogenous results, it has remained controversial which aspects of aneuploidy can drive CIN. In this study we systematically tested the impact of different types of aneuploidies on the induction of CIN. We generated a plethora of isogenic aneuploid clones harboring whole chromosome or segmental aneuploidies in human p53-deficient RPE-1 cells. We observed increased segregation errors in cells harboring trisomies that strongly correlated to the number of gained genes. Strikingly, we found that clones harboring only monosomies do not induce a CIN phenotype. Finally, we found that an initial chromosome breakage event and subsequent fusion can instigate breakage-fusion-bridge cycles in segmental aneuploidies. This suggests that monosomies, trisomies and segmental aneuploidies have fundamentally different effects on chromosomal instability and these results help us to decipher the complex relationship between aneuploidy and CIN.

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Systems approaches identify the consequences of monosomy in somatic human cells

Cited by 9 publications

References 64 publications

Proteogenomic analysis of aneuploidy reveals divergent types of gene expression regulation across cellular pathways

Proteogenomic analysis of aneuploidy reveals divergent types of gene expression regulation across cellular pathways

Extensive protein dosage compensation in aneuploid human cancers

Monosomies, trisomies and segmental aneuploidies differentially affect chromosomal stability

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