Cancer is driven by multiple types of genetic alterations, which range in size from point mutations to whole-chromosome gains and losses, known as aneuploidy. Chromosome instability, the process that ...gives rise to aneuploidy, can promote tumorigenesis by increasing genetic heterogeneity and promoting tumour evolution. However, much less is known about how aneuploidy itself contributes to tumour formation and progression. Unlike some pan-cancer oncogenes and tumour suppressor genes that drive transformation in virtually all cell types and cellular contexts, aneuploidy is not a universal promoter of tumorigenesis. Instead, recent studies suggest that aneuploidy is a context-dependent, cancer-type-specific oncogenic event that may have clinical relevance as a prognostic marker and as a potential therapeutic target.
Mitochondrial functions are essential for cell viability and rely on protein import into the organelle. Various disease and stress conditions can lead to mitochondrial import defects. We found that ...inhibition of mitochondrial import in budding yeast activated a surveillance mechanism, mitoCPR, that improved mitochondrial import and protected mitochondria during import stress. mitoCPR induced expression of Cis1, which associated with the mitochondrial translocase to reduce the accumulation of mitochondrial precursor proteins at the mitochondrial translocase. Clearance of precursor proteins depended on the Cis1-interacting AAA
adenosine triphosphatase Msp1 and the proteasome, suggesting that Cis1 facilitates degradation of unimported proteins. mitoCPR was required for maintaining mitochondrial functions when protein import was compromised, demonstrating the importance of mitoCPR in protecting the mitochondrial compartment.
Dividing cells that experience chromosome mis-segregation generate aneuploid daughter cells, which contain an incorrect number of chromosomes. Although aneuploidy interferes with the proliferation of ...untransformed cells, it is also, paradoxically, a hallmark of cancer, a disease defined by increased proliferative potential. These contradictory effects are also observed in mouse models of chromosome instability (CIN). CIN can inhibit and promote tumorigenesis. Recent work has provided insights into the cellular consequences of CIN and aneuploidy. Chromosome mis-segregation per se can alter the genome in many more ways than just causing the gain or loss of chromosomes. The short- and long-term effects of aneuploidy are caused by gene-specific effects and a stereotypic aneuploidy stress response. Importantly, these recent findings provide insights into the role of aneuploidy in tumorigenesis.
An unbalanced karyotype, a condition known as aneuploidy, has a profound impact on cellular physiology and is a hallmark of cancer. Aneuploid cells experience a number of stresses that are caused by ...aneuploidy-induced proteomic changes. How the aneuploidy-associated stresses affect cells and whether cells respond to them are only beginning to be understood. Here we show that autophagosomal cargo such as protein aggregates accumulate within lysosomes in aneuploid cells. This causes a lysosomal stress response. Aneuploid cells activate the transcription factor TFEB, a master regulator of autophagic and lysosomal gene expression, thereby increasing the expression of genes needed for autophagy-mediated protein degradation. Accumulation of autophagic cargo within the lysosome and activation of TFEB-responsive genes are also observed in cells in which proteasome function is inhibited, suggesting that proteotoxic stress causes TFEB activation. Our results reveal a TFEB-mediated lysosomal stress response as a universal feature of the aneuploid state.
Faithful inheritance of mitochondrial DNA (mtDNA) is crucial for cellular respiration/oxidative phosphorylation and mitochondrial membrane potential. However, how mtDNA is transmitted to progeny is ...not fully understood. We utilized hypersuppressive mtDNA, a class of respiratory deficient Saccharomyces cerevisiae mtDNA that is preferentially inherited over wild-type mtDNA (rho+), to uncover the factors governing mtDNA inheritance. We found that some regions of rho+ mtDNA persisted while others were lost after a specific hypersuppressive takeover indicating that hypersuppressive preferential inheritance may partially be due to active destruction of rho+ mtDNA. From a multicopy suppression screen, we found that overexpression of putative mitochondrial RNA exonuclease PET127 reduced biased inheritance of a subset of hypersuppressive genomes. This suppression required PET127 binding to the mitochondrial RNA polymerase RPO41 but not PET127 exonuclease activity. A temperature-sensitive allele of RPO41 improved rho+ mtDNA inheritance over a specific hypersuppressive mtDNA at semi-permissive temperatures revealing a previously unknown role for rho+ transcription in promoting hypersuppressive mtDNA inheritance.
Why haploinsufficiency persists Morrill, Summer A.; Amon, Angelika
Proceedings of the National Academy of Sciences - PNAS,
06/2019, Volume:
116, Issue:
24
Journal Article
Peer reviewed
Open access
Haploinsufficiency describes the decrease in organismal fitness observed when a single copy of a gene is deleted in diploids. We investigated the origin of haploinsufficiency by creating a ...comprehensive dosage sensitivity data set for genes under their native promoters. We demonstrate that the expression of haploinsufficient genes is limited by the toxicity of their overexpression. We further show that the fitness penalty associated with excess gene copy number is not the only determinant of haploinsufficiency. Haploin-sufficient genes represent a unique subset of genes sensitive to copy number increases, as they are also limiting for important cellular processes when present in one copy instead of two. The selective pressure to decrease gene expression due to the toxicity of overexpression, combined with the pressure to increase expression due to their fitness-limiting nature, has made haploinsufficient genes extremely sensitive to changes in gene expression. As a consequence, haploinsufficient genes are dosage stabilized, showing much more narrow ranges in cell-to-cell variability of expression compared with other genes in the genome. We propose a dosage-stabilizing hypothesis of haploinsufficiency to explain its persistence over evolutionary time.
Significance Aneuploidy refers to the gain or loss of individual chromosomes within a cell. Typically, aneuploidy is associated with detrimental consequences at both the cellular and organismal ...levels. However, reports of high levels of aneuploidy in the brain and liver suggested that aneuploidy might play a positive role in these organs. Here we use single cell sequencing to determine the prevalence of aneuploidy in somatic tissues. We find that aneuploidy is a rare occurrence in the liver and brain and is no more prevalent in these tissues than in skin. Our results demonstrate high karyotypic stability in somatic tissues, arguing against a role for aneuploidy in organ function and reinforcing its adverse effects at the cellular and organismal levels.
In budding yeast, the mitotic exit network (MEN), a GTPase signaling cascade, integrates spatial and temporal cues to promote exit from mitosis. This signal integration requires transmission of a ...signal generated on the cytoplasmic face of spindle pole bodies (SPBs; yeast equivalent of centrosomes) to the nucleolus, where the MEN effector protein Cdc14 resides. Here, we show that the MEN activating signal at SPBs is relayed to Cdc14 in the nucleolus through the dynamic localization of its terminal kinase complex Dbf2-Mob1. Cdc15, the protein kinase that activates Dbf2-Mob1 at SPBs, also regulates its nuclear access. Once in the nucleus, priming phosphorylation of Cfi1/Net1, the nucleolar anchor of Cdc14, by the Polo-like kinase Cdc5 targets Dbf2-Mob1 to the nucleolus. Nucleolar Dbf2-Mob1 then phosphorylates Cfi1/Net1 and Cdc14, activating Cdc14. The kinase-primed transmission of the MEN signal from the cytoplasm to the nucleolus exemplifies how signaling cascades can bridge distant inputs and responses.
Aneuploidy is frequently associated with disease and developmental abnormalities. It is also a key characteristic of cancer. Several model systems have been developed to study the role of chromosomal ...instability and aneuploidy in tumorigenesis. The results are surprisingly complex, with the conditions sometimes promoting and sometimes inhibiting tumour formation. Here, we review the effects of aneuploidy and chromosomal instability in cells and model systems of cancer, propose a model that could explain these complex findings and discuss how the aneuploid condition could be exploited in cancer therapy.
Aneuploidy is linked to developmental abnormalities and is predominant in cancer. This review explores the model systems that have informed our understanding of the role of aneuploidy in cancer, highlighting the complexity of the results and proposing a unifying model
Aneuploidy has a paradoxical effect on cell proliferation. In all normal cells analyzed to date, aneuploidy has been found to decrease the rate of cell proliferation. Yet, aneuploidy is also a ...hallmark of cancer, a disease of enhanced proliferative capacity, and aneuploid cells are frequently recovered following the experimental evolution of microorganisms. Thus, in certain contexts, aneuploidy might also have growth-advantageous properties. New models of aneuploidy and chromosomal instability have shed light on the diverse effects that karyotypic imbalances have on cellular phenotypes, and suggest novel ways of understanding the role of aneuploidy in development and disease.
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