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Nature Reviews. Cancer Mar 2023Dysregulated RNA splicing is a molecular feature that characterizes almost all tumour types. Cancer-associated splicing alterations arise from both recurrent mutations... (Review)
Review
Dysregulated RNA splicing is a molecular feature that characterizes almost all tumour types. Cancer-associated splicing alterations arise from both recurrent mutations and altered expression of trans-acting factors governing splicing catalysis and regulation. Cancer-associated splicing dysregulation can promote tumorigenesis via diverse mechanisms, contributing to increased cell proliferation, decreased apoptosis, enhanced migration and metastatic potential, resistance to chemotherapy and evasion of immune surveillance. Recent studies have identified specific cancer-associated isoforms that play critical roles in cancer cell transformation and growth and demonstrated the therapeutic benefits of correcting or otherwise antagonizing such cancer-associated mRNA isoforms. Clinical-grade small molecules that modulate or inhibit RNA splicing have similarly been developed as promising anticancer therapeutics. Here, we review splicing alterations characteristic of cancer cell transcriptomes, dysregulated splicing's contributions to tumour initiation and progression, and existing and emerging approaches for targeting splicing for cancer therapy. Finally, we discuss the outstanding questions and challenges that must be addressed to translate these findings into the clinic.
Topics: Humans; Alternative Splicing; RNA Splicing; Neoplasms; Protein Isoforms; Carcinogenesis; Cell Transformation, Neoplastic
PubMed: 36627445
DOI: 10.1038/s41568-022-00541-7 -
Nature Cancer May 2022High-throughput sequencing and functional characterization of the cancer transcriptome have uncovered cancer-specific dysregulation of RNA splicing across a variety of... (Review)
Review
High-throughput sequencing and functional characterization of the cancer transcriptome have uncovered cancer-specific dysregulation of RNA splicing across a variety of cancers. Alterations in the cancer genome and dysregulation of RNA splicing factors lead to missplicing, splicing alteration-dependent gene expression and, in some cases, generation of novel splicing-derived proteins. Here, we review recent advances in our understanding of aberrant splicing in cancer pathogenesis and present strategies to harness cancer-specific aberrant splicing for therapeutic intent.
Topics: Humans; Neoplasms; RNA Splicing; RNA Splicing Factors
PubMed: 35624337
DOI: 10.1038/s43018-022-00384-z -
Wiley Interdisciplinary Reviews. RNA Nov 2022Alternative RNA splicing increases transcript diversity in different cell types and under varying conditions. It is executed with the help of RNA splicing regulators... (Review)
Review
Alternative RNA splicing increases transcript diversity in different cell types and under varying conditions. It is executed with the help of RNA splicing regulators (RSRs), which are operationally defined as RNA-binding proteins (RBPs) that regulate alternative splicing, but not directly catalyzing the chemical reactions of splicing. By systematically searching for RBPs and manually identifying those that regulate splicing, we curated 305 RSRs in the human genome. Surprisingly, most of the RSRs are involved in neurogenesis. Among these RSRs, we focus on nine families (PTBP, NOVA, RBFOX, ELAVL, CELF, DBHS, MSI, PCBP, and MBNL) that play essential roles in the neurogenic pathway. A better understanding of their functions will provide novel insights into the role of splicing in brain development, health, and disease. This comprehensive review serves as a stepping-stone to explore the diverse and complex set of RSRs as fundamental regulators of neural development. This article is categorized under: RNA-Based Catalysis > RNA Catalysis in Splicing and Translation RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Processing > Splicing Regulation/Alternative Splicing.
Topics: Humans; RNA Splicing; Alternative Splicing; RNA-Binding Proteins; Neurogenesis; RNA
PubMed: 35388651
DOI: 10.1002/wrna.1728 -
Wiley Interdisciplinary Reviews. RNA Jan 2021Alternative splicing greatly expands the transcriptomic and proteomic diversities related to physiological and developmental processes in higher eukaryotes. Splicing of... (Review)
Review
Alternative splicing greatly expands the transcriptomic and proteomic diversities related to physiological and developmental processes in higher eukaryotes. Splicing of long noncoding RNAs, and back- and trans- splicing further expanded the regulatory repertoire of alternative splicing. RNA structures were shown to play an important role in regulating alternative splicing and back-splicing. Application of novel sequencing technologies made it possible to identify genome-wide RNA structures and interaction networks, which might provide new insights into RNA splicing regulation in vitro to in vivo. The emerging transcription-folding-splicing paradigm is changing our understanding of RNA alternative splicing regulation. Here, we review the insights into the roles and mechanisms of RNA structures in alternative splicing and back-splicing, as well as how disruption of these structures affects alternative splicing and then leads to human diseases. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems.
Topics: Alternative Splicing; Humans; Proteomics; RNA Splicing; RNA, Long Noncoding; Transcriptome
PubMed: 32929887
DOI: 10.1002/wrna.1626 -
Frontiers in Endocrinology 2021Alternative RNA splicing is a process by which introns are removed and exons are assembled to construct different RNA transcript isoforms from a single pre-mRNA.... (Review)
Review
Alternative RNA splicing is a process by which introns are removed and exons are assembled to construct different RNA transcript isoforms from a single pre-mRNA. Previous studies have demonstrated an association between dysregulation of RNA splicing and a number of clinical syndromes, but the generality to common disease has not been established. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease affecting one-third of adults worldwide, increasing the risk of cirrhosis and hepatocellular carcinoma (HCC). In this review we focus on the change in alternative RNA splicing in fatty liver disease and the role for splicing regulation in disease progression.
Topics: Adult; Alternative Splicing; Animals; Disease Progression; Genetic Predisposition to Disease; Humans; Liver; Non-alcoholic Fatty Liver Disease; RNA Splicing
PubMed: 33716968
DOI: 10.3389/fendo.2021.613213 -
Trends in Endocrinology and Metabolism:... Dec 2023The liver plays a key role in sensing nutritional and hormonal inputs to maintain metabolic homeostasis. Recent studies into pre-mRNA splicing and alternative splicing... (Review)
Review
The liver plays a key role in sensing nutritional and hormonal inputs to maintain metabolic homeostasis. Recent studies into pre-mRNA splicing and alternative splicing (AS) and their effects on gene expression have revealed considerable transcriptional complexity in the liver, both in health and disease. While the contribution of these mechanisms to cell and tissue identity is widely accepted, their role in physiological and pathological contexts within tissues is just beginning to be appreciated. In this review, we showcase recent studies on the splicing and AS of key genes in metabolic pathways in the liver, the effect of metabolic signals on the spliceosome, and therapeutic intervention points based on RNA splicing.
Topics: Humans; RNA Splicing; Alternative Splicing; Liver Diseases; Homeostasis
PubMed: 37673766
DOI: 10.1016/j.tem.2023.08.007 -
Molecules (Basel, Switzerland) Apr 2021RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is... (Review)
Review
RNA splicing is an essential step in producing mature messenger RNA (mRNA) and other RNA species. Harnessing RNA splicing modifiers as a new pharmacological modality is promising for the treatment of diseases caused by aberrant splicing. This drug modality can be used for infectious diseases by disrupting the splicing of essential pathogenic genes. Several antisense oligonucleotide splicing modifiers were approved by the U.S. Food and Drug Administration (FDA) for the treatment of spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Recently, a small-molecule splicing modifier, risdiplam, was also approved for the treatment of SMA, highlighting small molecules as important warheads in the arsenal for regulating RNA splicing. The cellular targets of these approved drugs are all mRNA precursors (pre-mRNAs) in human cells. The development of novel RNA-targeting splicing modifiers can not only expand the scope of drug targets to include many previously considered "undruggable" genes but also enrich the chemical-genetic toolbox for basic biomedical research. In this review, we summarized known splicing modifiers, screening methods for novel splicing modifiers, and the chemical space occupied by the small-molecule splicing modifiers.
Topics: Animals; Base Sequence; Disease; Drug Development; Drug Evaluation, Preclinical; Humans; RNA Splicing; Small Molecule Libraries; Spliceosomes
PubMed: 33919699
DOI: 10.3390/molecules26082263 -
Trends in Genetics : TIG Jan 2019Alternative splicing of pre-mRNA increases genetic diversity, and recent studies estimate that most human multiexon genes are alternatively spliced. If this process is... (Review)
Review
Alternative splicing of pre-mRNA increases genetic diversity, and recent studies estimate that most human multiexon genes are alternatively spliced. If this process is not highly regulated and accurate, it leads to mis-splicing events, which may result in proteins with altered function. A growing body of work has implicated mis-splicing events in a range of diseases, including cancer, neurodegenerative diseases, and muscular dystrophies. Understanding the mechanisms that cause aberrant splicing events and how this leads to disease is vital for designing effective therapeutic strategies. In this review, we focus on advances in therapies targeting splicing, and highlight the animal models developed to recapitulate disease phenotypes as a model for testing these therapies.
Topics: Alternative Splicing; Animals; Disease Models, Animal; Genetic Diseases, Inborn; Humans; Molecular Targeted Therapy; Mutation; RNA Precursors; RNA Splicing
PubMed: 30466729
DOI: 10.1016/j.tig.2018.10.002 -
Genes Jul 2021Almost all transcribed human genes undergo alternative RNA splicing, which increases the diversity of the coding and non-coding cellular landscape. The resultant gene... (Review)
Review
Almost all transcribed human genes undergo alternative RNA splicing, which increases the diversity of the coding and non-coding cellular landscape. The resultant gene products might have distinctly different and, in some cases, even opposite functions. Therefore, the abnormal regulation of alternative splicing plays a crucial role in malignant transformation, development, and progression, a fact supported by the distinct splicing profiles identified in both healthy and tumor cells. Drug resistance, resulting in treatment failure, still remains a major challenge for current cancer therapy. Furthermore, tumor cells often take advantage of aberrant RNA splicing to overcome the toxicity of the administered chemotherapeutic agents. Thus, deciphering the alternative RNA splicing variants in tumor cells would provide opportunities for designing novel therapeutics combating cancer more efficiently. In the present review, we provide a comprehensive outline of the recent findings in alternative splicing in the most common neoplasms, including lung, breast, prostate, head and neck, glioma, colon, and blood malignancies. Molecular mechanisms developed by cancer cells to promote oncogenesis as well as to evade anticancer drug treatment and the subsequent chemotherapy failure are also discussed. Taken together, these findings offer novel opportunities for future studies and the development of targeted therapy for cancer-specific splicing variants.
Topics: Alternative Splicing; Antineoplastic Agents; Carcinogenesis; Drug Resistance, Neoplasm; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Protein Isoforms; RNA; RNA Splicing; RNA, Messenger
PubMed: 34356101
DOI: 10.3390/genes12071085 -
Current Biology : CB
Review
Topics: Animals; Catalysis; Humans; RNA Splicing; RNA, Catalytic; RNA, Messenger; RNA, Small Nuclear; Ribonucleoproteins, Small Nuclear; Spliceosomes
PubMed: 9889110
DOI: 10.1016/s0960-9822(98)00005-0