Post-Translational Dosage Compensation Buffers Genetic Perturbations to Stoichiometry of Protein Complexes

Ishikawa, Kōji; Makanae, Koji; Iwasaki, Shigeo; Ingolia, Nicholas T.; Moriya, Hisao

doi:10.1371/journal.pgen.1006554

Cited by 72 publications

(101 citation statements)

References 63 publications

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“…It has been the basis of ribosome profiling experiments from recent studies associated with our laboratory, including but not limited to: Iwasaki et al [10], Werner et al [11], and Ishikawa et al [12]. In essence, the procedure is similar to that described in Ingolia et al (2012) [13]: cells are rapidly harvested and lysed under conditions that are expected to preserve in vivo ribosome positioning.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome-wide measurement of translation by ribosome profiling

McGlincy

Ingolia

2017

Methods

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435

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Translation is one of the fundamental processes of life. It comprises the assembly of polypeptides whose amino acid sequence corresponds to the codon sequence of an mRNA’s ORF. Translation is performed by the ribosome; therefore, in order to understand translation and its regulation we must be able to determine the numbers and locations of ribosomes on mRNAs in vivo. Furthermore, we must be able to examine their redistribution in different physiological contexts and in response to experimental manipulations. The ribosome profiling method provides us with an opportunity to learn these locations, by sequencing a cDNA library derived from the short fragments of mRNA covered by the ribosome. Since its original description, the ribosome profiling method has undergone continuing development; in this article we describe the method’s current state. Important improvements include: the incorporation of sample barcodes to enable library multiplexing, the incorporation of unique molecular identifiers to enable to removal of duplicated sequences, and the replacement of a gel-purification step with the enzymatic degradation of unligated linker.

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Section: Introductionmentioning

confidence: 99%

Transcriptome-wide measurement of translation by ribosome profiling

McGlincy

Ingolia

2017

Methods

Self Cite

435

504

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“…Several studies have shown that the majority of changes in gene copy number will propagate to changes in the corresponding protein levels (Dephoure et al, 2014;Pavelka et al, 2010;Stingele et al, 2012) . However, models of aneuploidy of different species and analysis of gene copy number variation (CNV) in cancer have shown that CNVs of protein coding genes belonging to protein complexes tend to be attenuated at protein level (Dephoure et al, 2014;Gonçalves et al, 2017;Ishikawa, Makanae, Iwasaki, Ingolia, & Moriya, 2017) . In addition we have shown that some complex members can act as rate-limiting subunits and indirectly control the degradation level of attenuated complex members .…”

Section: Introductionmentioning

confidence: 99%

Multi-omics characterization of interaction-mediated control of human protein abundance levels

Sousa

Gonçalvès

Mirauta

et al. 2018

Preprint

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Proteogenomic studies of cancer samples have shown that copy number variation can be attenuated at the protein level, for a large fraction of the proteome, likely due to the degradation of unassembled protein complex subunits. Such interaction mediated control of protein abundance remains poorly characterized. To study this we compiled genomic, (phospho)proteomic and structural data for hundreds of cancer samples and find that up to 42% of 8,124 analyzed proteins show signs of post-transcriptional control. We find evidence of interaction dependent control of protein abundance, correlated with interface size, for 516 protein pairs, with some interactions further controlled by phosphorylation. Finally, these findings in cancer were reflected in variation in protein levels in normal tissues. Importantly, expression differences due to natural genetic variation were increasingly buffered from phenotype differences for highly attenuated proteins. Altogether, this study further highlights the importance of post-transcriptional control of protein abundance in cancer and healthy cells.

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“…In fact, gene dosage compensation was mostly reported at the protein level and not at the transcriptional level, whereby the stoichiometry of protein complexes in aneuploid cells determines that excess subunits are either degraded or aggregated to achieve dosage compensation (Brennan et al, 2019) . Another work, using the genetic tug-of-war technique showed that approximately 10% of the genome shows gene dosage compensation at the protein level (Ishikawa et al, 2017), although this approach was not designed to distinguished compensation at the transcriptional level. To our knowledge, the only previous evidence of gene dosage compensation at the transcriptional level in cancer cells was provided for some few genes by a report of the insertion of an additional chromosome 5 (Stingele et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…The multiple consequences of aneuploidy are mainly regulated at the protein level due to a side-effect of protein folding defects and increased protein degradation by proteosome and autophagy (Donnelly & Storchová, 2014). An approach to identify genes with dosage compensation by increasing the copy number of individual genes using the genetic tug-of-war technique showed that approximately 10% of the genome shows gene dosage compensation, and consists predominantly of subunits of multi-protein complexes, which are regulated in a stoichiometry-dependent manner (Ishikawa, Makanae, Iwasaki, Ingolia, & Moriya, 2017), although this approach was designed to identify compensated genes at the protein level only.…”

Section: Introductionmentioning

confidence: 99%

Complex networks of miRNA-transcription factors mediate gene dosage compensation in aneuploid cancer

Acon

Oviedo

Baez

et al. 2020

Preprint

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Cancer complexity is consequence of enormous genomic instability leading to aneuploidy, a hallmark of most cancers. We hypothesize that dosage compensation of critical genes could arise from systems-level properties of complex networks of microRNAs (miRNA) and transcription factors (TF) as a way for cancer cells to withstand the negative effects of aneuploidy. We studied gene dosage compensation at the transcriptional level on data of the NCI-60 cancer cell line panel with the aid of computational models to identify candidate genes with low tolerance to variation in gene expression despite high variation in copy numbers. We identified a network of TF and miRNAs validated interactions with those genes to construct a mathematical model where the property of dosage compensation emerged for MYC and STAT3. Compensation was mediated by feedback and feed-forward motifs with 4 miRNAs and was dependent on the kinetic parameters of these TF-miRNA interactions, indicating that network analysis was not enough to identify this emergent property. The inhibition of miRNAs compensating MYC suggest a therapeutic potential of targeting gene dosage compensation against aneuploid cancer.

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Post-Translational Dosage Compensation Buffers Genetic Perturbations to Stoichiometry of Protein Complexes

Cited by 72 publications

References 63 publications

Transcriptome-wide measurement of translation by ribosome profiling

Transcriptome-wide measurement of translation by ribosome profiling

Multi-omics characterization of interaction-mediated control of human protein abundance levels

Complex networks of miRNA-transcription factors mediate gene dosage compensation in aneuploid cancer

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