Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy

Signal Transduction and Targeted Therapy, Год журнала: 2021, Номер 6(1)

Опубликована: Авг. 30, 2021

Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth proliferation. The ribosomal proteins (RPs), comprising the structural parts of ribosome, essential ribosome assembly function. In addition to their canonical functions, multiple RPs have extra-ribosomal functions including activation p53-dependent or p53-independent pathways in response stress, resulting cycle arrest apoptosis. Defects biogenesis, translation, individual RPs, mutations been linked a diverse range human congenital disorders termed ribosomopathies. Ribosomopathies characterized by tissue-specific phenotypic abnormalities higher cancer risk later life. Recent discoveries somatic tumor types reinforce connections between defects cancer. this article, we review most recent advances understanding molecular consequences RP ribosomopathies We particularly discuss basis transition from hypo- hyper-proliferation with elevated risk, paradox "Dameshek's riddle." Furthermore, current treatments prospective therapies targeting defects. also highlight stress-based therapeutics. Importantly, insights into mechanisms resistance bring new perspectives susceptibility clinical implications therapy.

Язык: Английский

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p53 at the crossroad of DNA replication and ribosome biogenesis stress pathways

Cell Death and Differentiation, Год журнала: 2022, Номер 29(5), С. 972 - 982

Опубликована: Апрель 20, 2022

Despite several decades of intense research focused on understanding function(s) and disease-associated malfunction p53, there is no sign any "mid-life crisis" in this rapidly advancing area biomedicine. Firmly established as the hub cellular stress responses tumor suppressor targeted most malignancies, p53's many talents continue to surprise us, providing not only fresh insights into cell organismal biology, but also new avenues cancer treatment. Among fruitful lines p53 recent years have been discoveries revealing multifaceted roles p53-centered pathways fundamental processes DNA replication ribosome biogenesis (RiBi), along with RiBi stresses, two intertwined areas (patho)physiology that we discuss review. Here, first provide concise introductory notes canonical key interacting proteins, downstream targets post-translational modifications involved regulation. We then highlight emerging involvement a component Fork Speed Regulatory Network mechanistic links checkpoint (RS), driving force cancer-associated genomic instability. Next, tantalizing, yet still rather foggy functional crosstalk between (nucleolar) stresses considered, followed by more defined p53-mediated monitoring multistep process RiBi, including latest updates RPL5/RPL11/5 S rRNA-MDM2-p53-mediated Impaired Ribosome Biogenesis Checkpoint (IRBC) pathway its tumorigenesis. The diverse defects IRBC predispose and/or contribute severe human pathologies developmental syndromes are outlined, examples promising small-molecule-based strategies therapeutically target RS- particularly RiBi- stress-tolerance mechanisms which cells addicted due their aberrant replication, repair, proteo-synthesis demands.

Язык: Английский

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A non-canonical role for a small nucleolar RNA in ribosome biogenesis and senescence

Cell, Год журнала: 2024, Номер 187(17), С. 4770 - 4789.e23

Опубликована: Июль 8, 2024

Cellular senescence is an irreversible state of cell-cycle arrest induced by various stresses, including aberrant oncogene activation, telomere shortening, and DNA damage. Through a genome-wide screen, we discovered conserved small nucleolar RNA (snoRNA), SNORA13, that required for multiple forms in human cells mice. Although SNORA13 guides the pseudouridylation nucleotide ribosomal decoding center, loss this snoRNA minimally impacts translation. Instead, found negatively regulates ribosome biogenesis. Senescence-inducing stress perturbs biogenesis, resulting accumulation free proteins (RPs) trigger p53 activation. interacts directly with RPL23, decreasing its incorporation into maturing 60S subunits and, consequently, increasing pool RPs, thereby promoting p53-mediated senescence. Thus, biogenesis pathway through non-canonical mechanism distinct from role guiding modification. These findings expand our understanding functions their roles cellular signaling.

Язык: Английский

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The Mettl3 epitranscriptomic writer amplifies p53 stress responses

Molecular Cell, Год журнала: 2022, Номер 82(13), С. 2370 - 2384.e10

Опубликована: Май 4, 2022

Язык: Английский

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The homeostatic regulation of ribosome biogenesis

Seminars in Cell and Developmental Biology, Год журнала: 2022, Номер 136, С. 13 - 26

Опубликована: Апрель 16, 2022

Язык: Английский

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Ribosome biogenesis and function in development and disease

Development, Год журнала: 2023, Номер 150(5)

Опубликована: Март 1, 2023

ABSTRACT Although differential transcription drives the development of multicellular organisms, ultimate readout a protein-coding gene is ribosome-dependent mRNA translation. Ribosomes were once thought as uniform molecular machines, but emerging evidence indicates that complexity and diversity ribosome biogenesis function should be given fresh look in context development. This Review begins with discussion different developmental disorders have been linked perturbations production function. We then highlight recent studies reveal how cells tissues exhibit variable levels protein synthesis, changes synthesis capacity can influence specific cell fate decisions. finish by touching upon heterogeneity stress responses These discussions importance considering both functional specialization disease.

Язык: Английский

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Specialized Ribosomes in Health and Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(7), С. 6334 - 6334

Опубликована: Март 28, 2023

Ribosomal heterogeneity exists within cells and between different cell types, at specific developmental stages, occurs in response to environmental stimuli. Mounting evidence supports the existence of specialized ribosomes, or changes ribosome that regulate translation a group transcripts. These alterations have been shown affect affinity ribosomes for certain mRNAs change cotranslational folding nascent polypeptides exit tunnel. The identification requires incorporation ribosomal proteins modifications rRNA and/or protein lead(s) physiologically relevant translation. In this review, we summarize specialization mammals discuss their relevance several human diseases.

Язык: Английский

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A stem cell roadmap of ribosome heterogeneity reveals a function for RPL10A in mesoderm production

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Сен. 19, 2022

Abstract Recent findings suggest that the ribosome itself modulates gene expression. However, whether ribosomes change composition across cell types or control fate remains unknown. Here, employing quantitative mass spectrometry during human embryonic stem differentiation, we identify dozens of changes underlying specification. We observe upregulation RPL10A/uL1-containing in primitive streak followed by progressive decreases mesoderm differentiation. An Rpl10a loss-of-function allele mice causes striking early mesodermal phenotypes, including posterior trunk truncations, and inhibits paraxial production culture. Ribosome profiling reveals decreased translation regulators, Wnt pathway mRNAs, which are also enriched on ribosomes. further show RPL10A/uL1 regulates canonical non-canonical signaling differentiation developing embryo. These reveal unexpected modularity controls development through specialized key networks.

Язык: Английский

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Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A

Blood, Год журнала: 2023, Номер unknown

Опубликована: Фев. 3, 2023

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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