Aneuploidy and proteotoxic stress in cancer

Although nearly ubiquitous in cancer, aneuploidy exerts detrimental effects on human cells. We recently demonstrated that aneuploid human cells exhibit impaired heat shock factor protein 1 (HSF1) and HSP90 function, suggesting a functional link between two recurring features of cancer cells: aneuploidy and proteotoxic stress. Further, our fi ndings implicate HSF1 as a key factor in mitigating the effects of aneuploid

Too much to differentiate: aneuploidy promotes proliferation and teratoma formation in embryonic stem cells

Aneuploidy, or an uneven number of chromosomes, has mostly detrimental consequences in eukaryotic cells, which include impaired proliferation as well as compromised DNA replication and protein folding. Unexpectedly, a new study published in this issue of The EMBO Journal shows that in murine embryonic stem cells aneuploidy does not interfere with proliferation, but rather hinders their differentiation capacity, thus propelling the formation of poorly differentiated teratomas

HIPK2 and extrachromosomal histone H2B are separately recruited by Aurora-B for cytokinesis

Cytokinesis, the final phase of cell division, is necessary to form two distinct daughter cells with correct distribution of genomic and cytoplasmic materials. Its failure provokes genetically unstable states, such as tetraploidization and polyploidization, which can contribute to tumorigenesis. Aurora-B kinase controls multiple cytokinetic events, from chromosome condensation to abscission when the midbody is severed. We have previously shown that HIPK2, a kinase involved in DNA damage response and development, localizes at the midbody and contributes to abscission by phosphorylating extrachromosomal histone H2B at Ser14. Of relevance, HIPK2-defective cells do not phosphorylate H2B and do not successfully complete cytokinesis leading to accumulation of binucleated cells, chromosomal instability, and increased tumorigenicity. However, how HIPK2 and H2B are recruited to the midbody during cytokinesis is still unknown. Here, we show that regardless of their direct (H2B) and indirect (HIPK2) binding of chromosomal DNA, both H2B and HIPK2 localize at the midbody independently of nucleic acids. Instead, by using mitotic kinase-specific inhibitors in a spatio-temporal regulated manner, we found that Aurora-B kinase activity is required to recruit both HIPK2 and H2B to the midbody. Molecular characterization showed that Aurora-B directly binds and phosphorylates H2B at Ser32 while indirectly recruits HIPK2 through the central spindle components MgcRacGAP and PRC1. Thus, among different cytokinetic functions, Aurora-B separately recruits HIPK2 and H2B to the midbody and these activities contribute to faithful cytokinesis

Consequences of Chromosome Loss:Why Do Cells Need Each Chromosome Twice?

Aneuploidy is a cellular state with an unbalanced chromosome number that deviates from the usual euploid status. During evolution, elaborate cellular mechanisms have evolved to maintain the correct chromosome content over generations. The rare errors often lead to cell death, cell cycle arrest, or impaired proliferation. At the same time, aneuploidy can provide a growth advantage under selective conditions in a stressful, frequently changing environment. This is likely why aneuploidy is commonly found in cancer cells, where it correlates with malignancy, drug resistance, and poor prognosis. To understand this "aneuploidy paradox", model systems have been established and analyzed to investigate the consequences of aneuploidy. Most of the evidence to date has been based on models with chromosomes gains, but chromosome losses and recurrent monosomies can also be found in cancer. We summarize the current models of chromosome loss and our understanding of its consequences, particularly in comparison to chromosome gains

РОЗВИТОК СИСТЕМИ ВМІНЬ І НАВИЧОК СТУДЕНТІВ-ГЕРМАНІСТІВ ЗАСОБАМИ ЛАТИНСЬКОЇ МОВИ

The article is devoted to the problem of competent approach to forming the content of Germanic student’s philological education by means of the Latin language. The correlation of linguistic competence (LC) and speech practice is observed, the limits of LC have been determined. It was proved that studying Latin on the primary stage of forming philological thinking is the necessary means of knowledge systematization. Components of linguistic competence were investigated, habits and skills formed by means of Latin were determined and classified.Стаття призначена проблемі компетентнісного підходу до формування змісту філологічної освіти студента-германіста засобами латинської мови. Розглянуто співвідношення мовної та лінгвістичної компетенції та визначено межі лінгвістичної компетенції навчальної дисципліни «Латинська мова». Доведено, що вивчення латинської мови на початковому етапі формування філологічного мислення студента-германіста виступає необхідним засобом систематизації знань.У статті досліджено складники лінгвістичної компетенції студента-германіста, визначено та класифіковано навички та уміння, що формуються засобами латини

Mol. Syst. Biol.

Extra chromosome copies markedly alter the physiology of eukaryotic cells, but the underlying reasons are not well understood. We created human trisomic and tetrasomic cell lines and determined the quantitative changes in their transcriptome and proteome in comparison with their diploid counterparts. We found that whereas transcription levels reflect the chromosome copy number changes, the abundance of some proteins, such as subunits of protein complexes and protein kinases, is reduced toward diploid levels. Furthermore, using the quantitative data we investigated the changes of cellular pathways in response to aneuploidy. This analysis revealed specific and uniform alterations in pathway regulation in cells with extra chromosomes. For example, the DNA and RNA metabolism pathways were downregulated, whereas several pathways such as energy metabolism, membrane metabolism and lysosomal pathways were upregulated. In particular, we found that the p62-dependent selective autophagy is activated in the human trisomic and tetrasomic cells. Our data present the first broad proteomic analysis of human cells with abnormal karyotypes and suggest a uniform cellular response to the presence of an extra chromosome

Unique features of the transcriptional response to model aneuploidy in human cells

Background: Aneuploidy, a karyotype deviating from multiples of a haploid chromosome set, affects the physiology of eukaryotes. In humans, aneuploidy is linked to pathological defects such as developmental abnormalities, mental retardation or cancer, but the underlying mechanisms remain elusive. There are many different types and origins of aneuploidy, but whether there is a uniform cellular response to aneuploidy in human cells has not been addressed so far. Results: Here we evaluate the transcription profiles of eleven trisomic and tetrasomic cell lines and two cell lines with complex aneuploid karyotypes. We identify a characteristic aneuploidy response pattern defined by upregulation of genes linked to endoplasmic reticulum, Golgi apparatus and lysosomes, and downregulation of DNA replication, transcription as well as ribosomes. Strikingly, complex aneuploidy elicits the same transcriptional changes as trisomy. To uncover the triggers of the response, we compared the profiles with transcription changes in human cells subjected to stress conditions. Interestingly, we found an overlap only with the response to treatment with the autophagy inhibitor bafilomycin A1. Finally, we identified 23 genes whose expression is significantly altered in all aneuploids and which may thus serve as aneuploidy markers. Conclusions: Our analysis shows that despite the variability in chromosome content, aneuploidy triggers uniform transcriptional response in human cells. A common response independent of the type of aneuploidy might be exploited as a novel target for cancer therapy. Moreover, the potential aneuploidy markers identified in our analysis might represent novel biomarkers to assess the malignant potential of a tumor

Control of Transcription by Cell Size

Cell size increases significantly with increasing ploidy. Differences in cell size and ploidy are associated with alterations in gene expression, although no direct connection has been made between cell size and transcription. Here we show that ploidy-associated changes in gene expression reflect transcriptional adjustment to a larger cell size, implicating cellular geometry as a key parameter in gene regulation. Using RNA-seq, we identified genes whose expression was altered in a tetraploid as compared with the isogenic haploid. A significant fraction of these genes encode cell surface proteins, suggesting an effect of the enlarged cell size on the differential regulation of these genes. To test this hypothesis, we examined expression of these genes in haploid mutants that also produce enlarged size. Surprisingly, many genes differentially regulated in the tetraploid are identically regulated in the enlarged haploids, and the magnitude of change in gene expression correlates with the degree of size enlargement. These results indicate a causal relationship between cell size and transcription, with a size-sensing mechanism that alters transcription in response to size. The genes responding to cell size are enriched for those regulated by two mitogen-activated protein kinase pathways, and components in those pathways were found to mediate size-dependent gene regulation. Transcriptional adjustment to enlarged cell size could underlie other cellular changes associated with polyploidy. The causal relationship between cell size and transcription suggests that cell size homeostasis serves a regulatory role in transcriptome maintenance.National Institutes of Health (U.S.) (grant GM035010)National Institutes of Health (U.S.) (grant GM040266