RNA-binding proteins in human genetic disease

Nature Reviews Genetics, Год журнала: 2020, Номер 22(3), С. 185 - 198

Опубликована: Ноя. 24, 2020

Язык: Английский

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Alternative splicing and cancer: a systematic review

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

Опубликована: Фев. 24, 2021

Abstract The abnormal regulation of alternative splicing is usually accompanied by the occurrence and development tumors, which would produce multiple different isoforms diversify protein expression. aim present study was to conduct a systematic review in order describe regulatory mechanisms splicing, as well its functions tumor cells, from proliferation apoptosis invasion metastasis, angiogenesis metabolism. events contributed progression oncogenic drivers and/or bystander factors. alterations factors detected tumors other mis-splicing (i.e., long non-coding circular RNAs) tumorigenesis were also included. findings recent therapeutic approaches targeting catalysis proteins modulate pathogenically spliced (including tumor-specific neo-antigens for cancer immunotherapy) introduced. emerging RNA-based strategies treatment with abnormally discussed. However, further studies are still required address association between more detail.

Язык: Английский

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RNA splicing dysregulation and the hallmarks of cancer

Nature reviews. Cancer, Год журнала: 2023, Номер 23(3), С. 135 - 155

Опубликована: Янв. 10, 2023

Язык: Английский

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Phase Separation as a Missing Mechanism for Interpretation of Disease Mutations

Cell, Год журнала: 2020, Номер 183(7), С. 1742 - 1756

Опубликована: Дек. 1, 2020

Язык: Английский

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The role of alternative splicing in cancer: From oncogenesis to drug resistance

Drug Resistance Updates, Год журнала: 2020, Номер 53, С. 100728 - 100728

Опубликована: Сен. 28, 2020

Alternative splicing is a tightly regulated process whereby non-coding sequences of pre-mRNA are removed and protein-coding segments assembled in diverse combinations, ultimately giving rise to proteins with distinct or even opposing functions. In the past decade, whole genome/transcriptome sequencing studies revealed high complexity regulation, which occurs co-transcriptionally influenced by chromatin status mRNA modifications. Consequently, profiles both healthy malignant cells display diversity alternative was shown be widely deregulated multiple cancer types. particular, mutations regulatory sequences, regulators modifiers, as well differential expression factors important contributors pathogenesis. It has become clear that these aberrations contribute many facets cancer, including oncogenic transformation, progression, response anticancer drug treatment resistance therapy. this respect, perturb broad spectrum relevant genes involved uptake/metabolism (i.e. SLC29A1, dCK, FPGS, TP), activation nuclear receptor pathways GR, AR), regulation apoptosis MCL1, BCL-X, FAS) modulation immunotherapy (CD19). Furthermore, aberrant constitutes an source novel biomarkers spliceosome machinery represents attractive target for rapidly expanding class therapeutic agents. Small molecule inhibitors targeting SF3B1 splice factor kinases were highly cytotoxic against wide range models, drug-resistant cells. Importantly, effects enhanced specific subsets, such factor-mutated c-MYC-driven tumors. pre-clinical report synergistic modulators combination conventional antitumor These strategies based on use low dose could shift window towards decreased toxicity tissues. Here we provide extensive overview latest findings field molecular mechanisms harness drive oncogenesis evade splicing-based vulnerabilities can opportunities. discuss current challenges arising from genome-wide detection prediction methods splicing, unravelling functional relevance plethora cancer-related alterations.

Язык: Английский

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PRMT5 function and targeting in cancer

Cell Stress, Год журнала: 2020, Номер 4(8), С. 199 - 215

Опубликована: Июль 24, 2020

Protein methyl transferases play critical roles in numerous regulatory pathways that underlie cancer development, progression and therapy-response. Here we discuss the function of PRMT5, a member nine-member PRMT family, controlling oncogenic processes including tumor intrinsic, as well extrinsic microenvironmental signaling pathways. We PRMT5 effect on histone methylation proteins those involved RNA splicing, cell cycle, death metabolic signaling. In all, highlight importance regulation cancer, which provide foundation for therapeutic modalities targeting PRMT5.

Язык: Английский

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Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals

Genome biology, Год журнала: 2021, Номер 22(1)

Опубликована: Янв. 14, 2021

Abstract Background Alternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies plants have investigated AS response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, comprehensive study contrasting stress-response tissue-specific patterns directly comparing them with those animal models still missing. Results We generate massive resource for Arabidopsis thaliana , PastDB comprising expression quantifications across tissues, development including abiotic biotic stresses. Harmonized analysis these datasets reveals A. shows high levels AS, similar fruitflies, that, compared animals, disproportionately uses stress responses. identify core sets genes regulated specifically by either or transcription upon stresses among specialization tightly mirrored the genomic features genes. Unexpectedly, non-intron events, exon skipping, are overrepresented being also largely involved modulating through NMD uORF inclusion. Conclusions Non-intron events likely been functionally underrated plants. constitutes distinct layer controlling internal external stimuli whose target master regulators hardwired at level undergo post-transcriptional regulation. Given higher relevance different when this molecular hardwiring required proper .

Язык: Английский

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Regulation of pre-mRNA splicing: roles in physiology and disease, and therapeutic prospects

Nature Reviews Genetics, Год журнала: 2022, Номер 24(4), С. 251 - 269

Опубликована: Дек. 16, 2022

Язык: Английский

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Noncoding RNAs regulate alternative splicing in Cancer

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

Опубликована: Янв. 6, 2021

Abstract AS (alternative splicing) is a fundamental process by which gene can generate multiple distinct mRNA transcripts to increase protein diversity. Defects in influence the occurrence and development of many diseases, including cancers, are frequently found participate various aspects cancer biology, such as promoting invasion, metastasis, apoptosis resistance drug resistance. NcRNAs (noncoding RNAs) an abundant class RNAs that do not encode proteins. include miRNAs (microRNAs), lncRNAs (long noncoding RNAs), circRNAs (circular snRNAs (small nuclear have been proven act regulatory molecules mediate processes through AS. directly or indirectly plethora molecular targets regulate cis-acting elements, trans-acting factors, pre-mRNA transcription at levels, affecting generating alternatively spliced isoforms. Consequently, ncRNA-mediated outcomes affect cellular signaling pathways promote suppress progression. In this review, we summarize current mechanisms ncRNAs cancers discuss their potential clinical applications biomarkers therapeutic targets.

Язык: Английский

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The Many Facets of Therapy Resistance and Tumor Recurrence in Glioblastoma

Cells, Год журнала: 2021, Номер 10(3), С. 484 - 484

Опубликована: Фев. 24, 2021

Glioblastoma (GBM) is the most lethal type of primary brain cancer. Standard care using chemo- and radio-therapy modestly increases overall survival patients; however, recurrence inevitable, due to treatment resistance lack response targeted therapies. GBM therapy has been attributed several extrinsic intrinsic factors which affect dynamics tumor evolution physiology thus creating clinical challenges. Tumor-intrinsic such as heterogeneity, hypermutation, altered metabolomics oncologically activated alternative splicing pathways change landscape facilitate failure progression. Moreover, tumor-extrinsic hypoxia an immune-suppressive microenvironment (TME) are chief causes immunotherapy in GBM. Amid success other cancers, occurred a model resistance, focusing current efforts on not only alleviating immunotolerance but also evading escape mechanisms cells therapy, caused by inter- intra-tumoral heterogeneity. Here we review various GBM, continuously evolving well complex TME, cumulatively contribute malignancy failure; attempt understand identify effective therapies for recurrent

Язык: Английский

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