Effects of aneuploidy on cell behaviour and function

Nature Reviews Molecular Cell Biology, Год журнала: 2022, Номер 23(4), С. 250 - 265

Опубликована: Янв. 5, 2022

Язык: Английский

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Cell competition in development, homeostasis and cancer

Nature Reviews Molecular Cell Biology, Год журнала: 2022, Номер 24(3), С. 221 - 236

Опубликована: Сен. 29, 2022

Язык: Английский

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Cell competition: emerging signaling and unsolved questions

FEBS Letters, Год журнала: 2024, Номер 598(4), С. 379 - 389

Опубликована: Фев. 1, 2024

Multicellular communities have an intrinsic mechanism that optimizes their structure and function via cell–cell communication. One of the driving forces for such self‐organization multicellular system is cell competition, elimination viable unfit or deleterious cells interaction. Studies in Drosophila mammals identified multiple mechanisms competition caused by different types mutations cellular changes. Intriguingly, recent studies found “losers” commonly show reduced protein synthesis. In , reduction synthesis levels loser phosphorylation translation initiation factor eIF2α a bZip transcription Xrp1. Given variety stresses converge on thus global inhibition synthesis, may be machinery fitness removing stressed cells. this review, we summarize discuss emerging signaling critical unsolved questions, as well role competition.

Язык: Английский

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The transcription factor Xrp1 orchestrates both reduced translation and cell competition upon defective ribosome assembly or function

eLife, Год журнала: 2022, Номер 11

Опубликована: Фев. 18, 2022

Ribosomal Protein ( Rp ) gene haploinsufficiency affects translation rate, can lead to protein aggregation, and causes cell elimination by competition with wild type cells in mosaic tissues. We find that the modest changes ribosomal subunit levels observed were insufficient for these effects, which all depended on AT-hook, bZip domain Xrp1. Xrp1 reduced global through PERK-dependent phosphorylation of eIF2α. eIF2α was itself sufficient enable otherwise cells, but expression, not as downstream effector Unexpectedly, many other defects reducing ribosome biogenesis or function (depletion TAF1B, eIF2, eIF4G, eIF6, eEF2, eEF1α1, eIF5A), also increased enabled competition. This expression induced depletions. In absence Xrp1, differences between themselves trigger is shown here be a sequence-specific transcription factor regulates transposable elements well single-copy genes. Thus, master regulator triggers multiple consequences stresses key instigator

Язык: Английский

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The sculpting of somatic mutational landscapes by evolutionary forces and their impacts on aging‐related disease

Molecular Oncology, Год журнала: 2022, Номер 16(18), С. 3238 - 3258

Опубликована: Июнь 21, 2022

Aging represents the major risk factor for development of cancer and many other diseases. Recent findings show that normal tissues become riddled with expanded clones are frequently driven by cancer‐associated mutations in an aging‐dependent fashion. Additional studies how aged tissue microenvironments promote initiation progression malignancies, while young healthy actively suppress outgrowth malignant clones. Here, we discuss conserved mechanisms eliminate poorly functioning or potentially cells from our to maintain organismal health fitness. Natural selection acts preserve function prevent disease maximize reproductive success but these wane as reproduction becomes less likely. The ensuing age‐dependent decline can impact shape direction clonal somatic evolution, lifestyle exposures influencing its pace intensity. We also consider aging‐ exposure‐dependent expansions “oncogenic” might both increase late life contribute non‐malignant disease. Still, marvel at ability bodies avoid cancers diseases despite accumulation billions mutations.

Язык: Английский

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A multi-omics genome-and-transcriptome single-cell atlas of human preimplantation embryogenesis reveals the cellular and molecular impact of chromosome instability

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 10, 2023

ABSTRACT The frequent acquisition of genomic abnormalities in human preimplantation embryos is a leading cause pregnancy loss, but does not necessarily prohibit healthy offspring. However, the impact on cellular states and development early embryo remains largely unclear. Here, we characterise aneuploidy reconstruct gene regulatory networks embryos, investigate expression developmental perturbations instigated by using single-cell genome-and-transcriptome sequencing (G&T-seq). At level, show that acquired numerical structural chromosomal aberrations are across all stages embryogenesis cell lineages. transcriptome identify regulators identity uncover network 248 transcription factors from 10 major modules distinct lineages embryos. By integrating DNA-with RNA-information, unveil how levels affected losses or gains corresponding genes embryonic cells development, as well copy-number aberrant factor perturb their cognate target euploid regions. Furthermore, reveal majority aneuploid delay reduced fitness, indicating competition within mosaic diploid-aneuploid embryo, which may contribute to selection against birth offspring In summary, our multi-modal analyses provide unprecedented insights into development.

Язык: Английский

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The Duality of Caspases in Cancer, as Told through the Fly

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(16), С. 8927 - 8927

Опубликована: Авг. 19, 2021

Caspases, a family of cysteine-aspartic proteases, have an established role as critical components in the activation and initiation apoptosis. Alongside this variety non-apoptotic caspase functions proliferation, differentiation, cellular plasticity cell migration been reported. The activity level context are important factors determining function. As consequence their apoptosis beyond, caspases uniquely situated to pathological roles, including cancer. Altered function is common trait cancers, with apoptotic evasion defined "hallmark cancer". However, that play cancer much more complex, acting both prevent promote tumourigenesis. This review focuses on major findings

Язык: Английский

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Mitigating age-related somatic mutation burden

Trends in Molecular Medicine, Год журнала: 2023, Номер 29(7), С. 530 - 540

Опубликована: Апрель 29, 2023

Genomes are inherently unstable and require constant DNA repair to maintain their genetic information. However, selective pressure has optimized mechanisms in somatic cells only allow transmitting information the next generation, not maximize sequence integrity long beyond reproductive age. Recent studies have confirmed that mutations, due errors during genome replication, accumulate tissues organs of humans model organisms. Here, we describe recent advances quantitative analysis mutations vivo. We also review evidence for or against a possible causal role aging. Finally, discuss options prevent, delay eliminate de novo, random as cause

Язык: Английский

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Ribosomal protein mutations and cell competition: autonomous and nonautonomous effects on a stress response

Genetics, Год журнала: 2023, Номер 224(3)

Опубликована: Июнь 2, 2023

Abstract Ribosomal proteins (Rps) are essential for viability. Genetic mutations affecting Rp genes were first discovered in Drosophila, where they represent a major class of haploinsufficient mutations. One mutant copy gives rise to the dominant “Minute” phenotype, characterized by slow growth and small, thin bristles. Wild-type (WT) Minute cells compete mosaics, that is, Rp+/− preferentially lost when their neighbors wild-type genotype. Many features gene haploinsufficiency (i.e. phenotypes) mediated transcriptional program. In reduced translation under control Xrp1, bZip-domain transcription factor induced leads ultimately phosphorylation eIF2α consequently inhibition most translation. phenotypes also transcriptionally yeast mammals. mammals, Impaired Ribosome Biogenesis Checkpoint activates p53. Recent findings link other cellular stresses, including DNA damage response endoplasmic reticulum stress. We suggest cell competition results from nonautonomous inputs stress responses, bringing decisions between adaptive apoptotic outcomes influence nearby cells. eliminates aneuploid which loss chromosome haploinsufficiency. The effects on whole organism, flies or humans with Diamond-Blackfan Anemia, may be inevitable consequences pathways useful eliminating individual mosaics. Alternatively, apparently deleterious organism might adaptive, preventing even more detrimental outcomes. example, p53 activation appears suppress oncogenic

Язык: Английский

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Cell competition and the regulation of protein homeostasis

Current Opinion in Cell Biology, Год журнала: 2024, Номер 87, С. 102323 - 102323

Опубликована: Фев. 1, 2024

The process of embryonic development involves remarkable cellular plasticity, which governs the coordination between cells necessary to build an organism. One role this plasticity is ensure that when aberrant are eliminated, growth adjustment occurs so size tissue maintained. An important regulator ensures cooperation a fitness-sensing mechanism termed cell competition. During competition, with defects lower fitness but do not affect viability, such as those cause impaired signal transduction, slower growth, mitochondrial dysregulation or protein homeostasis, killed surrounded by fitter cells. This accompanied compensatory proliferation surviving underlying factors and mechanisms demarcate certain less fit than their neighbouring losers competition still relatively unknown. Recent evidence has pointed proteotoxic stress hallmarks these loser Here, we review recent advances in area, focussing on activity homeostasis major determining competitive during importance proteostasis fitness.

Язык: Английский

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