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1.
Cell ; 186(9): 1985-2001.e19, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-37075754

RESUMO

Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer. Here, we describe KaryoCreate (karyotype CRISPR-engineered aneuploidy technology), a system that enables the generation of chromosome-specific aneuploidies by co-expression of an sgRNA targeting chromosome-specific CENPA-binding ɑ-satellite repeats together with dCas9 fused to mutant KNL1. We design unique and highly specific sgRNAs for 19 of the 24 chromosomes. Expression of these constructs leads to missegregation and induction of gains or losses of the targeted chromosome in cellular progeny, with an average efficiency of 8% for gains and 12% for losses (up to 20%) validated across 10 chromosomes. Using KaryoCreate in colon epithelial cells, we show that chromosome 18q loss, frequent in gastrointestinal cancers, promotes resistance to TGF-ß, likely due to synergistic hemizygous deletion of multiple genes. Altogether, we describe an innovative technology to create and study chromosome missegregation and aneuploidy in the context of cancer and beyond.


Assuntos
Centrômero , Técnicas Genéticas , Humanos , Aneuploidia , Centrômero/genética , Deleção Cromossômica , Neoplasias/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas
2.
Cell ; 186(15): 3166-3181.e18, 2023 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-37413989

RESUMO

Proper preimplantation development is essential to assemble a blastocyst capable of implantation. Live imaging has uncovered major events driving early development in mouse embryos; yet, studies in humans have been limited by restrictions on genetic manipulation and lack of imaging approaches. We have overcome this barrier by combining fluorescent dyes with live imaging to reveal the dynamics of chromosome segregation, compaction, polarization, blastocyst formation, and hatching in the human embryo. We also show that blastocyst expansion mechanically constrains trophectoderm cells, causing nuclear budding and DNA shedding into the cytoplasm. Furthermore, cells with lower perinuclear keratin levels are more prone to undergo DNA loss. Moreover, applying trophectoderm biopsy, a mechanical procedure performed clinically for genetic testing, increases DNA shedding. Thus, our work reveals distinct processes underlying human development compared with mouse and suggests that aneuploidies in human embryos may not only originate from chromosome segregation errors during mitosis but also from nuclear DNA shedding.


Assuntos
Diagnóstico Pré-Implantação , Gravidez , Feminino , Humanos , Animais , Camundongos , Diagnóstico Pré-Implantação/métodos , Blastocisto , Implantação do Embrião , Testes Genéticos/métodos , Aneuploidia , Biópsia/métodos
3.
Cell ; 185(16): 2988-3007.e20, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35858625

RESUMO

Human cleavage-stage embryos frequently acquire chromosomal aneuploidies during mitosis due to unknown mechanisms. Here, we show that S phase at the 1-cell stage shows replication fork stalling, low fork speed, and DNA synthesis extending into G2 phase. DNA damage foci consistent with collapsed replication forks, DSBs, and incomplete replication form in G2 in an ATR- and MRE11-dependent manner, followed by spontaneous chromosome breakage and segmental aneuploidies. Entry into mitosis with incomplete replication results in chromosome breakage, whole and segmental chromosome errors, micronucleation, chromosome fragmentation, and poor embryo quality. Sites of spontaneous chromosome breakage are concordant with sites of DNA synthesis in G2 phase, locating to gene-poor regions with long neural genes, which are transcriptionally silent at this stage of development. Thus, DNA replication stress in mammalian preimplantation embryos predisposes gene-poor regions to fragility, and in particular in the human embryo, to the formation of aneuploidies, impairing developmental potential.


Assuntos
Quebra Cromossômica , Segregação de Cromossomos , Aneuploidia , Animais , DNA , Replicação do DNA , Desenvolvimento Embrionário/genética , Humanos , Mamíferos/genética
4.
Cell ; 184(11): 2860-2877.e22, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33964210

RESUMO

Most human embryos are aneuploid. Aneuploidy frequently arises during the early mitotic divisions of the embryo, but its origin remains elusive. Human zygotes that cluster their nucleoli at the pronuclear interface are thought to be more likely to develop into healthy euploid embryos. Here, we show that the parental genomes cluster with nucleoli in each pronucleus within human and bovine zygotes, and clustering is required for the reliable unification of the parental genomes after fertilization. During migration of intact pronuclei, the parental genomes polarize toward each other in a process driven by centrosomes, dynein, microtubules, and nuclear pore complexes. The maternal and paternal chromosomes eventually cluster at the pronuclear interface, in direct proximity to each other, yet separated. Parental genome clustering ensures the rapid unification of the parental genomes on nuclear envelope breakdown. However, clustering often fails, leading to chromosome segregation errors and micronuclei, incompatible with healthy embryo development.


Assuntos
Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/genética , Aneuploidia , Animais , Bovinos , Nucléolo Celular/metabolismo , Núcleo Celular/metabolismo , Centrossomo/metabolismo , Segregação de Cromossomos/fisiologia , Cromossomos/metabolismo , Fertilização/genética , Humanos , Masculino , Microtúbulos/metabolismo , Mitose , Oócitos/metabolismo , Espermatozoides/metabolismo , Zigoto/metabolismo
5.
Nat Rev Mol Cell Biol ; 24(1): 27-44, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36068367

RESUMO

During fertilization, the egg and the sperm are supposed to contribute precisely one copy of each chromosome to the embryo. However, human eggs frequently contain an incorrect number of chromosomes - a condition termed aneuploidy, which is much more prevalent in eggs than in either sperm or in most somatic cells. In turn, aneuploidy in eggs is a leading cause of infertility, miscarriage and congenital syndromes. Aneuploidy arises as a consequence of aberrant meiosis during egg development from its progenitor cell, the oocyte. In human oocytes, chromosomes often segregate incorrectly. Chromosome segregation errors increase in women from their mid-thirties, leading to even higher levels of aneuploidy in eggs from women of advanced maternal age, ultimately causing age-related infertility. Here, we cover the two main areas that contribute to aneuploidy: (1) factors that influence the fidelity of chromosome segregation in eggs of women from all ages and (2) factors that change in response to reproductive ageing. Recent discoveries reveal new error-causing pathways and present a framework for therapeutic strategies to extend the span of female fertility.


Assuntos
Infertilidade , Sêmen , Animais , Feminino , Masculino , Humanos , Oócitos/metabolismo , Aneuploidia , Meiose , Envelhecimento/genética , Segregação de Cromossomos/genética , Infertilidade/metabolismo , Mamíferos
6.
Nat Rev Mol Cell Biol ; 23(4): 250-265, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34987171

RESUMO

Aneuploidy, a genomic alternation characterized by deviations in the copy number of chromosomes, affects organisms from early development through to aging. Although it is a main cause of human pregnancy loss and a hallmark of cancer, how aneuploidy affects cellular function has been elusive. The last two decades have seen rapid advances in the understanding of the causes and consequences of aneuploidy at the molecular and cellular levels. These studies have uncovered effects of aneuploidy that can be beneficial or detrimental to cells and organisms in an environmental context-dependent and karyotype-dependent manner. Aneuploidy also imposes general stress on cells that stems from an imbalanced genome and, consequently, also an imbalanced proteome. These insights provide the fundamental framework for understanding the impact of aneuploidy in genome evolution, human pathogenesis and drug resistance.


Assuntos
Aneuploidia , Proteoma , Fenômenos Fisiológicos Celulares , Cromossomos , Genômica , Humanos , Proteoma/genética
7.
Cell ; 179(5): 1207-1221.e22, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31730858

RESUMO

Accurate measurement of clonal genotypes, mutational processes, and replication states from individual tumor-cell genomes will facilitate improved understanding of tumor evolution. We have developed DLP+, a scalable single-cell whole-genome sequencing platform implemented using commodity instruments, image-based object recognition, and open source computational methods. Using DLP+, we have generated a resource of 51,926 single-cell genomes and matched cell images from diverse cell types including cell lines, xenografts, and diagnostic samples with limited material. From this resource we have defined variation in mitotic mis-segregation rates across tissue types and genotypes. Analysis of matched genomic and image measurements revealed correlations between cellular morphology and genome ploidy states. Aggregation of cells sharing copy number profiles allowed for calculation of single-nucleotide resolution clonal genotypes and inference of clonal phylogenies and avoided the limitations of bulk deconvolution. Finally, joint analysis over the above features defined clone-specific chromosomal aneuploidy in polyclonal populations.


Assuntos
Replicação do DNA/genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Análise de Célula Única , Aneuploidia , Animais , Ciclo Celular/genética , Linhagem Celular Tumoral , Forma Celular , Sobrevivência Celular , Cromossomos Humanos/genética , Células Clonais , Elementos de DNA Transponíveis/genética , Diploide , Feminino , Genótipo , Humanos , Masculino , Camundongos , Mutação/genética , Filogenia , Polimorfismo de Nucleotídeo Único/genética
8.
Cell ; 173(2): 283-285, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625045

RESUMO

The Cancer Genome Atlas (TCGA) team now presents the Pan-Cancer Atlas, investigating different aspects of cancer biology by analyzing the data generated during the 10+ years of the TCGA project.


Assuntos
Bases de Dados Genéticas , Genes Neoplásicos , Neoplasias/patologia , Aneuploidia , Genoma Humano , Humanos , Mutação , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/metabolismo
9.
Cell ; 173(2): 291-304.e6, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625048

RESUMO

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.


Assuntos
Neoplasias/patologia , Aneuploidia , Cromossomos/genética , Análise por Conglomerados , Ilhas de CpG , Metilação de DNA , Bases de Dados Factuais , Humanos , MicroRNAs/metabolismo , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , RNA Mensageiro/metabolismo
10.
Cell ; 173(2): 386-399.e12, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29625054

RESUMO

The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on "chromatin-state" to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.


Assuntos
Elementos Facilitadores Genéticos/genética , Neoplasias/patologia , Aneuploidia , Antígeno B7-H1/genética , Cromatina/genética , Cromatina/metabolismo , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/terapia , Análise de Sequência de RNA , Taxa de Sobrevida
11.
Cell ; 174(6): 1347-1360, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30193109

RESUMO

Chromosomal instability (CIN) is a hallmark of human cancer, and it is associated with poor prognosis, metastasis, and therapeutic resistance. CIN results from errors in chromosome segregation during mitosis, leading to structural and numerical chromosomal abnormalities. In addition to generating genomic heterogeneity that acts as a substrate for natural selection, CIN promotes inflammatory signaling by introducing double-stranded DNA into the cytosol, engaging the cGAS-STING anti-viral pathway. These multipronged effects distinguish CIN as a central driver of tumor evolution and as a genomic source for the crosstalk between the tumor and its microenvironment, in the course of immune editing and evasion.


Assuntos
Instabilidade Cromossômica , Aneuploidia , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Nucleotidiltransferases/metabolismo , Transdução de Sinais , Microambiente Tumoral
12.
Cell ; 173(2): 499-514.e23, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29576454

RESUMO

Genomics has provided a detailed structural description of the cancer genome. Identifying oncogenic drivers that work primarily through dosage changes is a current challenge. Unrestrained proliferation is a critical hallmark of cancer. We constructed modular, barcoded libraries of human open reading frames (ORFs) and performed screens for proliferation regulators in multiple cell types. Approximately 10% of genes regulate proliferation, with most performing in an unexpectedly highly tissue-specific manner. Proliferation drivers in a given cell type showed specific enrichment in somatic copy number changes (SCNAs) from cognate tumors and helped predict aneuploidy patterns in those tumors, implying that tissue-type-specific genetic network architectures underlie SCNA and driver selection in different cancers. In vivo screening confirmed these results. We report a substantial contribution to the catalog of SCNA-associated cancer drivers, identifying 147 amplified and 107 deleted genes as potential drivers, and derive insights about the genetic network architecture of aneuploidy in tumors.


Assuntos
Aneuploidia , Neoplasias/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Mapeamento Cromossômico , Cromossomos/genética , Fator de Transcrição E2F1/antagonistas & inibidores , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Feminino , Biblioteca Gênica , Genômica , Humanos , Queratinas/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Oncogenes , Fases de Leitura Aberta/genética , Interferência de RNA , RNA Interferente Pequeno/metabolismo
13.
Cell ; 168(6): 977-989.e17, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28262352

RESUMO

Meiosis is the cellular program that underlies gamete formation. For this program, crossovers between homologous chromosomes play an essential mechanical role to ensure regular segregation. We present a detailed study of crossover formation in human male and female meiosis, enabled by modeling analysis. Results suggest that recombination in the two sexes proceeds analogously and efficiently through most stages. However, specifically in female (but not male), ∼25% of the intermediates that should mature into crossover products actually fail to do so. Further, this "female-specific crossover maturation inefficiency" is inferred to make major contributions to the high level of chromosome mis-segregation and resultant aneuploidy that uniquely afflicts human female oocytes (e.g., giving Down syndrome). Additionally, crossover levels on different chromosomes in the same nucleus tend to co-vary, an effect attributable to global per-nucleus modulation of chromatin loop size. Maturation inefficiency could potentially reflect an evolutionary advantage of increased aneuploidy for human females.


Assuntos
Aneuploidia , Cromossomos Humanos , Meiose , Caracteres Sexuais , Núcleo Celular/genética , Feminino , Gametogênese , Humanos , Masculino , Recombinação Genética
14.
Cell ; 169(2): 229-242.e21, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28388408

RESUMO

Phenotypic variability is a hallmark of diseases involving chromosome gains and losses, such as Down syndrome and cancer. Allelic variances have been thought to be the sole cause of this heterogeneity. Here, we systematically examine the consequences of gaining and losing single or multiple chromosomes to show that the aneuploid state causes non-genetic phenotypic variability. Yeast cell populations harboring the same defined aneuploidy exhibit heterogeneity in cell-cycle progression and response to environmental perturbations. Variability increases with degree of aneuploidy and is partly due to gene copy number imbalances, suggesting that subtle changes in gene expression impact the robustness of biological networks and cause alternate behaviors when they occur across many genes. As inbred trisomic mice also exhibit variable phenotypes, we further propose that non-genetic individuality is a universal characteristic of the aneuploid state that may contribute to variability in presentation and treatment responses of diseases caused by aneuploidy.


Assuntos
Aneuploidia , Heterogeneidade Genética , Fenótipo , Animais , Ciclo Celular , Divisão Celular , Dano ao DNA , Regulação da Expressão Gênica , Cinética , Camundongos , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/genética
15.
Cell ; 167(3): 803-815.e21, 2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-27720452

RESUMO

Do young and old protein molecules have the same probability to be degraded? We addressed this question using metabolic pulse-chase labeling and quantitative mass spectrometry to obtain degradation profiles for thousands of proteins. We find that >10% of proteins are degraded non-exponentially. Specifically, proteins are less stable in the first few hours of their life and stabilize with age. Degradation profiles are conserved and similar in two cell types. Many non-exponentially degraded (NED) proteins are subunits of complexes that are produced in super-stoichiometric amounts relative to their exponentially degraded (ED) counterparts. Within complexes, NED proteins have larger interaction interfaces and assemble earlier than ED subunits. Amplifying genes encoding NED proteins increases their initial degradation. Consistently, decay profiles can predict protein level attenuation in aneuploid cells. Together, our data show that non-exponential degradation is common, conserved, and has important consequences for complex formation and regulation of protein abundance.


Assuntos
Estabilidade Proteica , Proteínas/metabolismo , Proteólise , Alanina/análogos & derivados , Alanina/química , Aneuploidia , Linhagem Celular , Química Click , Amplificação de Genes , Humanos , Cinética , Cadeias de Markov , Complexo de Endopeptidases do Proteassoma/química , Biossíntese de Proteínas , Proteínas/química , Proteínas/genética , Proteoma , Ubiquitina/química
16.
Cell ; 166(3): 567-581, 2016 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-27374329

RESUMO

Insulin signaling regulates many facets of animal physiology. Its dysregulation causes diabetes and other metabolic disorders. The spindle checkpoint proteins MAD2 and BUBR1 prevent precocious chromosome segregation and suppress aneuploidy. The MAD2 inhibitory protein p31(comet) promotes checkpoint inactivation and timely chromosome segregation. Here, we show that whole-body p31(comet) knockout mice die soon after birth and have reduced hepatic glycogen. Liver-specific ablation of p31(comet) causes insulin resistance, hyperinsulinemia, glucose intolerance, and hyperglycemia and diminishes the plasma membrane localization of the insulin receptor (IR) in hepatocytes. MAD2 directly binds to IR and facilitates BUBR1-dependent recruitment of the clathrin adaptor AP2 to IR. p31(comet) blocks the MAD2-BUBR1 interaction and prevents spontaneous clathrin-mediated IR endocytosis. BUBR1 deficiency enhances insulin sensitivity in mice. BUBR1 depletion in hepatocytes or the expression of MAD2-binding-deficient IR suppresses the metabolic phenotypes of p31(comet) ablation. Our findings establish a major IR regulatory mechanism and link guardians of chromosome stability to nutrient metabolism.


Assuntos
Pontos de Checagem do Ciclo Celular , Insulina/metabolismo , Mitose , Transdução de Sinais , Complexo 2 de Proteínas Adaptadoras/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Aneuploidia , Animais , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Segregação de Cromossomos , Clatrina/metabolismo , Endocitose , Células Hep G2 , Homeostase , Humanos , Resistência à Insulina , Fígado/metabolismo , Proteínas Mad2/metabolismo , Camundongos , Camundongos Knockout , Proteínas Nucleares , Proteínas Serina-Treonina Quinases/metabolismo , Receptor de Insulina/metabolismo
17.
Genes Dev ; 37(5-6): 171-190, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36859339

RESUMO

Both the presence of an abnormal complement of chromosomes (aneuploidy) and an increased frequency of chromosome missegregation (chromosomal instability) are hallmarks of cancer. Analyses of cancer genome data have identified certain aneuploidy patterns in tumors; however, the bases behind their selection are largely unexplored. By establishing time-resolved long-term adaptation protocols, we found that human cells adapt to persistent spindle assembly checkpoint (SAC) inhibition by acquiring specific chromosome arm gains and losses. Independently adapted populations converge on complex karyotypes, which over time are refined to contain ever smaller chromosomal changes. Of note, the frequencies of chromosome arm gains in adapted cells correlate with those detected in cancers, suggesting that our cellular adaptation approach recapitulates selective traits that dictate the selection of aneuploidies frequently observed across many cancer types. We further engineered specific aneuploidies to determine the genetic basis behind the observed karyotype patterns. These experiments demonstrated that the adapted and engineered aneuploid cell lines limit CIN by extending mitotic duration. Heterozygous deletions of key SAC and APC/C genes recapitulated the rescue phenotypes of the monosomic chromosomes. We conclude that aneuploidy-induced gene dosage imbalances of individual mitotic regulators are sufficient for altering mitotic timing to reduce CIN.


Assuntos
Pontos de Checagem da Fase M do Ciclo Celular , Neoplasias , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/genética , Aneuploidia , Neoplasias/genética , Instabilidade Cromossômica/genética , Cariótipo , Fuso Acromático/genética , Mitose
18.
Annu Rev Genet ; 56: 369-390, 2022 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-36055648

RESUMO

Meiosis, a key process in the creation of haploid gametes, is a complex cellular division incorporating unique timing and intricate chromosome dynamics. Abnormalities in this elaborate dance can lead to the production of aneuploid gametes, i.e., eggs containing an incorrect number of chromosomes, many of which cannot generate a viable pregnancy. For many decades, research has been attempting to address why this process is notoriously error prone in humans compared to many other organisms. Rapidly developing technologies, access to new clinical material, and a mounting public infertility crisis have kept the field both active and quickly evolving. In this review, we discuss the history of aneuploidy in humans with a focus on its origins in maternal meiosis. We also gather current working mechanistic hypotheses, as well as up-and-coming areas of interest that point to future scientific avenues and their potential clinical applications.


Assuntos
Aneuploidia , Células Germinativas , Feminino , Gravidez , Humanos , Meiose/genética , Haploidia
19.
Cell ; 160(4): 771-784, 2015 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-25679766

RESUMO

Aneuploid genomes, characterized by unbalanced chromosome stoichiometry (karyotype), are associated with cancer malignancy and drug resistance of pathogenic fungi. The phenotypic diversity resulting from karyotypic diversity endows the cell population with superior adaptability. We show here, using a combination of experimental data and a general stochastic model, that the degree of phenotypic variation, thus evolvability, escalates with the degree of overall growth suppression. Such scaling likely explains the challenge of treating aneuploidy diseases with a single stress-inducing agent. Instead, we propose the design of an "evolutionary trap" (ET) targeting both karyotypic diversity and fitness. This strategy entails a selective condition "channeling" a karyotypically divergent population into one with a predominant and predictably drugable karyotypic feature. We provide a proof-of-principle case in budding yeast and demonstrate the potential efficacy of this strategy toward aneuploidy-based azole resistance in Candida albicans. By analyzing existing pharmacogenomics data, we propose the potential design of an ET against glioblastoma.


Assuntos
Aneuploidia , Candida albicans/efeitos dos fármacos , Candida albicans/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Antifúngicos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Linhagem Celular Tumoral , Farmacorresistência Fúngica , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/antagonistas & inibidores , Fluconazol/farmacologia , Humanos , Higromicina B/farmacologia , Irinotecano , Saccharomyces cerevisiae/metabolismo
20.
Nature ; 630(8015): 149-157, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38778096

RESUMO

Accessing the natural genetic diversity of species unveils hidden genetic traits, clarifies gene functions and allows the generalizability of laboratory findings to be assessed. One notable discovery made in natural isolates of Saccharomyces cerevisiae is that aneuploidy-an imbalance in chromosome copy numbers-is frequent1,2 (around 20%), which seems to contradict the substantial fitness costs and transient nature of aneuploidy when it is engineered in the laboratory3-5. Here we generate a proteomic resource and merge it with genomic1 and transcriptomic6 data for 796 euploid and aneuploid natural isolates. We find that natural and lab-generated aneuploids differ specifically at the proteome. In lab-generated aneuploids, some proteins-especially subunits of protein complexes-show reduced expression, but the overall protein levels correspond to the aneuploid gene dosage. By contrast, in natural isolates, more than 70% of proteins encoded on aneuploid chromosomes are dosage compensated, and average protein levels are shifted towards the euploid state chromosome-wide. At the molecular level, we detect an induction of structural components of the proteasome, increased levels of ubiquitination, and reveal an interdependency of protein turnover rates and attenuation. Our study thus highlights the role of protein turnover in mediating aneuploidy tolerance, and shows the utility of exploiting the natural diversity of species to attain generalizable molecular insights into complex biological processes.


Assuntos
Aneuploidia , Complexo de Endopeptidases do Proteassoma , Proteólise , Proteoma , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Mecanismo Genético de Compensação de Dose , Variação Genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Proteoma/metabolismo , Proteoma/genética , Proteômica , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Ubiquitinação , Perfilação da Expressão Gênica , Genômica
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