Evolutionary adaptation to hyperstable microtubules selectively targets tubulins and is empowered by the spindle assembly checkpoint

Cell Reports, Год журнала: 2025, Номер 44(2), С. 115323 - 115323

Опубликована: Фев. 1, 2025

Microtubules are polymers required for chromosome segregation. Their drug-induced hyperstabilization impairs segregation and is an established anti-cancer therapy. How cells respond to microtubule hyperstabilization, however, incompletely understood. To study this, we evolved budding yeast expressing a microtubule-hyperstabilizing tubulin mutant isolated adapted strains. Aneuploidy of specific chromosomes carrying the regulators STU2 VIK1/KAR3 was first observable adaptation. In longer run, aneuploidies were outcompeted by mutations in α- or β-tubulin, partially overlapping with cancer patients. Thus, compensation follows restrained reproducible path where new combine original offending mutation on same carrier. While partly compensatory, several failed re-establish fully normal dynamics. Sustained growth relied mitotic checkpoint, indicating that extended timing limits genomic instability caused reduced Our results predict potential vulnerability resistant agents.

Язык: Английский

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Replication catastrophe is responsible for intrinsic PAR glycohydrolase inhibitor-sensitivity in patient-derived ovarian cancer models

Journal of Experimental & Clinical Cancer Research, Год журнала: 2021, Номер 40(1)

Опубликована: Окт. 16, 2021

Abstract Background Patients with ovarian cancer often present at advanced stage and, following initial treatment success, develop recurrent drug-resistant disease. PARP inhibitors (PARPi) are yielding unprecedented survival benefits for women BRCA-deficient However, options remain limited disease that is platinum-resistant and/or has inherent or acquired PARPi-resistance. PARG, the PAR glycohydrolase counterbalances activity, an emerging target potential to selectively kill tumour cells harbouring oncogene-induced DNA replication and metabolic vulnerabilities. Clinical development of PARG (PARGi) will however require predictive biomarkers, in turn requiring understanding their mode action. Furthermore, differential sensitivity PARPi key expanding available patients. Methods A panel 10 cell lines a living biobank patient-derived models (OCMs) were screened PARGi-sensitivity using short- long-term growth assays. was characterized established markers stress, namely fibre asymmetry, RPA foci, KAP1 Chk1 phosphorylation, pan-nuclear γH2AX, indicating catastrophe. Finally, gene expression sensitive resistant also examined NanoString RNAseq. Results PARGi identified both OCMs, accompanied by persistent pre-mitotic cycle block. Moreover, genes down-regulated PARGi-sensitive consistent vulnerability. did not predict OCMs. The subset OCMs single-agent inhibition, includes PARPi- platinum-resistant, may represent alternative strategy otherwise therapeutic options. Conclusions We discover cancers intrinsically pharmacological blockade, including disease, underpinned common mechanism explore use transcript-based biomarker, provide insight into design future clinical trials patients cancer. our results highlight complexity developing biomarker sensitivity.

Язык: Английский

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Evolutionary repair: Changes in multiple functional modules allow meiotic cohesin to support mitosis

PLoS Biology, Год журнала: 2020, Номер 18(3), С. e3000635 - e3000635

Опубликована: Март 10, 2020

The role of proteins often changes during evolution, but we do not know how cells adapt when a protein is asked to participate in different biological function. We forced the budding yeast, Saccharomyces cerevisiae, use meiosis-specific kleisin, recombination 8 (Rec8), mitotic cell cycle, instead its paralog, Scc1. This perturbation impairs sister chromosome linkage, advances timing genome replication, and reduces reproductive fitness by 45%. evolved 15 parallel populations for 1,750 generations, substantially increasing their fitness, analyzed genotypes phenotypes cells. Only one population contained mutation Rec8, many had mutations transcriptional mediator complex, cohesin-related genes, cycle regulators that induce S phase. These improve cohesion delay replication Rec8-expressing conclude known novel partners allow an existing new functions.

Язык: Английский

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Experimental evolution for cell biology

Trends in Cell Biology, Год журнала: 2023, Номер 33(11), С. 903 - 912

Опубликована: Май 15, 2023

Evolutionary cell biology explores the origins, principles, and core functions of cellular features regulatory networks through lens evolution. This emerging field relies heavily on comparative experiments genomic analyses that focus exclusively extant diversity historical events, providing limited opportunities for experimental validation. In this opinion article, we explore potential laboratory evolution to augment evolutionary toolbox, drawing inspiration from recent studies combine with biological assays. Primarily focusing approaches single cells, provide a generalizable template adapting protocols fresh insight into long-standing questions in biology.

Язык: Английский

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Epistasis, aneuploidy, and functional mutations underlie evolution of resistance to induced microtubule depolymerization

The EMBO Journal, Год журнала: 2021, Номер 40(22)

Опубликована: Окт. 4, 2021

Язык: Английский

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Mechanisms used by cancer cells to tolerate drug-induced replication stress

Cancer Letters, Год журнала: 2022, Номер 544, С. 215804 - 215804

Опубликована: Июнь 22, 2022

Activation of oncogenes in cancer cells forces cell proliferation, leading to DNA replication stress (RS). As a consequence, heavily rely on the intra S-phase checkpoint for survival. This fundamental principle formed basis development inhibitors against key players checkpoint, ATR and CHK1. These drugs are often combined with chemotherapeutic that interfere exacerbate RS exhaust cells. However, drug resistance impedes efficient clinical use, suggesting some tolerate severe RS. In this review, we describe how an increased nucleotide pool, boosted stabilization repair stalled forks firing dormant origins fortify response Notably, vast majority genes confer tolerance regulated by E2F NRF2 transcription factors. transcriptional programs frequently activated cells, allowing simultaneous activation multiple avenues. We propose can be used as biomarker select patients treatment RS-inducing novel targets kill RS-tolerant Together, review aims provide framework maximally exploit Achilles' heel

Язык: Английский

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Comparative Gene Expression Analysis Reveals Mechanism of Pinus contorta Response to the Fungal Pathogen Dothistroma septosporum

Molecular Plant-Microbe Interactions, Год журнала: 2020, Номер 34(4), С. 397 - 409

Опубликована: Дек. 1, 2020

Many conifers have distributions that span wide ranges in both biotic and abiotic conditions, but the basis of response to stress has received much less attention than stress. In this study, we investigated gene expression lodgepole pine (Pinus contorta) attack by fungal pathogen Dothistroma septosporum, which causes needle blight, a disease caused severe climate-related outbreaks northwestern British Columbia. We inoculated tolerant susceptible pines with two D. septosporum isolates analyzed differentially expressed genes (DEGs), differential exon usage, coexpressed modules using RNA-sequencing data. found rapid strong transcriptomic samples one isolate, late weak another isolate. mapped 43 DEG- or module–identified reference plant-pathogen interaction pathway deposited Kyoto Encyclopedia Genes Genomes database. These are present PAMP-triggered effector-triggered immunity pathways. comprising pathways had signatures selective constraint, while highly appear been favored selection counterattack pathogen. identified candidate resistance may respond effectors. Taken together, our results show infection varies among tree genotypes strains involves known number previously unknown functions. [Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under CC BY-NC-ND 4.0 International license .

Язык: Английский

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Evolutionary Divergence in DNA Damage Responses among Fungi

mBio, Год журнала: 2021, Номер 12(2)

Опубликована: Март 16, 2021

Cell cycle checkpoints and DNA repair pathways contribute to maintaining genome integrity are thought be evolutionarily ancient broadly conserved. For example, in the yeast Saccharomyces cerevisiae humans, damage induces activation of a checkpoint effector kinase, Rad53p (human homolog Chk2), promote cell arrest transcription genes. However, recent studies have revealed variation response networks some fungi. Shor et al. (mBio 11:e03044-20, 2020, https://doi.org/10.1128/mBio.03044-20) demonstrate that comparison S. cerevisiae, fungal pathogen Candida glabrata has reduced damage. Consequently, downstream targets maintenance, such as polymerases, transcriptionally downregulated C. Downregulation maintenance genes likely contributes higher rates mitotic failure death This other findings highlight evolutionary diversity eukaryotic responses.

Язык: Английский

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Ploidy and recombination proficiency shape the evolutionary adaptation to constitutive DNA replication stress

PLoS Genetics, Год журнала: 2021, Номер 17(11), С. e1009875 - e1009875

Опубликована: Ноя. 9, 2021

In haploid budding yeast, evolutionary adaptation to constitutive DNA replication stress alters three genome maintenance modules: replication, the damage checkpoint, and sister chromatid cohesion. We asked how these trajectories depend on genomic features by comparing in strains: haploids, diploids, recombination deficient haploids. all three, happens within 1000 generations at rates that are correlated with initial fitness defect of ancestors. Mutations individual genes selected different frequencies populations features, but benefits mutations confer similar strains, combinations reproduce gains evolved populations. Despite differences mutations, targets same functional modules strains revealing a common response stress.

Язык: Английский

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Adaptive and pleiotropic effects of evolution in synonymous sugar environments

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 30, 2024

Abstract Adaptation to an environment is enabled by the accumulation of beneficial mutations. When adapted populations are shifted other environments, byproduct or pleiotropic fitness effects these mutations can be wide-ranged. Since there exists no molecular framework quantify relatedness predicting based on adaptation has been challenging. In this work, we ask if evolution in highly similar environments elicits correlated adaptive and responses. We evolve replicate Escherichia coli non-stressful that contain either a mixture glucose galactose, lactose, melibiose as source carbon. term sugars “synonymous”, since lactose disaccharides made up galactose. Therefore, differed only way carbon was presented bacterial population. After 300 generations evolution, see responses not predictable. investigate range non-synonymous show despite uncorrelated changes, nature largely predictable ancestor non-home environments. Overall, our results highlight how subtle changes alter adaptation, but sequence-level variations, pleiotropy qualitatively Lay Summary nature, “similar” believed elicit identical For example, arctic fox ptarmigan, which two unrelated species living arctic, have evolved turn white winters. They did ability because they from common ancestor, favoured trait. what happens evolving minute environment, consequences adapting “almost identical”, call them, “synonymous”. bacteria E. three synonymous their grow both does proceed fashion populations, each favours different However, interestingly, sets perform almost identically, growth Our even simple act drivers biodiversity.

Язык: Английский

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