4.7 Review

Reprogramming RNA processing: an emerging therapeutic landscape

Related references

Note: Only part of the references are listed.
Article Oncology

SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance

Kristen Jensen-Pergakes et al.

Summary: Protein arginine methyltransferase 5 (PRMT5) is overexpressed in hematologic and solid tumors, and its methyltransferase function is associated with tumor cell proliferation and overall survival. The discovery of potent and selective PRMT5 inhibitors, such as PF-06939999, has provided a potential approach for targeting cancer-specific dependencies. Inhibition of PRMT5 by PF-06939999 reduces proliferation and affects alternative splicing in non-small cell lung cancer (NSCLC) cells. The efficacy of PF-06939999 in mouse tumor xenograft models with splicing mutations suggests its therapeutic potential in the treatment of NSCLC with splicing dysregulation.

MOLECULAR CANCER THERAPEUTICS (2022)

Review Cell Biology

Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression

Lori A. Passmore et al.

Summary: Recent studies have shown that poly(A) tails play a complex role in the cytoplasm, including promoting translation and controlling mRNA stability through deadenylation. The length of poly(A) tails is correlated with translation rate and mRNA lifespan, indicating a significant role in gene regulation.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2022)

Review Cell Biology

Alternative polyadenylation: An enigma of transcript length variation in health and disease

Neeraja K. Mohanan et al.

Summary: Alternative polyadenylation (APA) is a molecular mechanism involving multiple polyadenylation sites in pre-mRNA processing, leading to transcripts of varying lengths from a single gene. APA plays a crucial role in transcript length, coding potential, and protein function, and is considered an important regulatory mechanism in the pathophysiology of human diseases. Targeting APA regulators could have therapeutic significance in combatting drug resistance in cancer and other complex diseases.

WILEY INTERDISCIPLINARY REVIEWS-RNA (2022)

Article Multidisciplinary Sciences

Widespread occurrence of hybrid internal-terminal exons in human transcriptomes

Ana Fiszbein et al.

Summary: Messenger RNA isoform differences are mainly driven by alternative first, internal, and last exons. A recent study identified hybrid exons, which are enriched in long genes and genes involved in RNA splicing, and showed their usage varies considerably across human tissues. The HIT pipeline was developed to classify exons and reveal the common occurrence of hybrid exons in the human transcriptome.

SCIENCE ADVANCES (2022)

Article Biochemistry & Molecular Biology

Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer

Elizabeth A. Bowling et al.

Summary: This study reveals that mis-spliced RNA can trigger tumor cell death through viral mimicry, where dsRNA-binding proteins recognize mis-spliced RNA and induce antiviral signaling and apoptosis. Additionally, the findings suggest that STTs may activate anti-tumor immune pathways by responding to global aberrations of RNA splicing in cancer.
Article Multidisciplinary Sciences

Structure of a transcribing RNA polymerase II-U1 snRNP complex

Suyang Zhang et al.

Summary: The study revealed that RNA polymerase II interacts directly with U1 small nuclear ribonucleoprotein particle, facilitating the positioning of the pre-mRNA splice site and the formation of an intron loop to aid in spliceosome assembly.

SCIENCE (2021)

Article Multidisciplinary Sciences

PRMT5 inhibition disrupts splicing and stemness in glioblastoma

Patty Sachamitr et al.

Summary: The study suggests that PRMT5 inhibitors can block the growth of patient-derived glioblastoma stem cell cultures in vitro and in vivo, indicating that PRMT5 inhibition may be a useful therapeutic strategy.

NATURE COMMUNICATIONS (2021)

Article Multidisciplinary Sciences

Small molecule splicing modifiers with systemic HTT-lowering activity

Anuradha Bhattacharyya et al.

Summary: The authors describe the discovery of small molecule splicing modifiers that can be taken orally, cross the blood-brain barrier, and lower levels of huntingtin in a mouse model of Huntington's disease. These modifiers act by selectively modulating pre-messenger RNA splicing to reduce huntingtin expression throughout the brain and body.

NATURE COMMUNICATIONS (2021)

Article Biochemistry & Molecular Biology

Cotranscriptional splicing efficiencies differ within genes and between cell types

Karan Bedi et al.

Summary: This study investigated cotranscriptional splicing efficiencies of 17,000 introns expressed across six human cell lines using Bru-seq and BruChase-seq. Less than half of all introns were found to be cotranscriptionally spliced. The efficiency of splicing varied across cell lines and within genes, and was not correlated with gene length, intron position, splice site strengths, or GC content. Binding signals from RNA-binding proteins were found to correlate with splicing efficiency, suggesting their important roles in determining splicing outcomes in a cell type- and intron-specific manner.
Review Genetics & Heredity

Anything but Ordinary - Emerging Splicing Mechanisms in Eukaryotic Gene Regulation

Niels H. Gehring et al.

Summary: Splicing of precursor mRNAs is essential for eukaryotic gene expression, with accurate identification of splice sites and intron removal being crucial for producing desired mRNA isoforms. Recent research has uncovered noncanonical splicing mechanisms that play key roles in gene expression regulation, in addition to well-understood basic splicing regulation mechanisms.

TRENDS IN GENETICS (2021)

Article Biochemistry & Molecular Biology

Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

Sydney X. Lu et al.

Summary: The study demonstrates that modulation of splicing through specific drug classes generates genuine neoantigens and enhances anti-tumor immunity, augmenting checkpoint immunotherapy.
Review Biochemistry & Molecular Biology

Oncogenic dysregulation of pre-mRNA processing by protein kinases: challenges and therapeutic opportunities

Chiara Naro et al.

Summary: Alternative splicing and polyadenylation play crucial roles in the diversification of the human transcriptome and proper gene expression. Dysregulation of these processes can contribute to oncogenesis and treatment resistance in cancer. Protein kinase families such as SRPK, CLK, and CDK are key players in fine-tuning pre-mRNA processing mechanisms, and their inhibition has shown anticancer effects in cancer cells.

FEBS JOURNAL (2021)

Article Oncology

Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms

David P. Steensma et al.

Summary: H3B-8800 treatment was associated with mostly low-grade treatment-related adverse events and induced red blood cell transfusion independence in a subset of MDS patients.

LEUKEMIA (2021)

Article Multidisciplinary Sciences

Structural basis of intron selection by U2 snRNP in the presence of covalent inhibitors

Constantin Cretu et al.

Summary: Chemical modulation of intron selection has emerged as a route for cancer therapy. The structures of the U2 snRNP's SF3B module and prespliceosome - both in complexes with splicing modulators - provide insight into the mechanisms of intron recognition and branch site inactivation.

NATURE COMMUNICATIONS (2021)

Article Multidisciplinary Sciences

Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia

Masahiko Ajiro et al.

Summary: Research has shown that the small molecule splice modulator RECTAS can enhance the inclusion of exon 20 of the IKBKAP gene causing familial dysautonomia by promoting the binding of the splicing enhancer factor SRSF6. RECTAS interacts with CDC-like kinases (CLKs) and enhances SRSF6 phosphorylation to achieve its effects. By regulating cellular CLK activity, RECTAS can bidirectionally manipulate exon 20 splicing, which has been validated in multiple FD disease models.

NATURE COMMUNICATIONS (2021)

Article Multidisciplinary Sciences

A deep learning approach to identify gene targets of a therapeutic for human splicing disorders

Dadi Gao et al.

Summary: Pre-mRNA splicing is crucial for human gene expression control, and disturbances in splicing due to mutation can lead to dysregulated protein expression. The identified SMC, BPN-15477, corrects splicing defects caused by mutations in specific genes, increasing functional protein levels, demonstrating its clinical potential for treating genetic diseases. The use of deep learning strategies to predict drug targets for RNA splicing modulation shows promise for expanding therapeutic potential.

NATURE COMMUNICATIONS (2021)

Article Biochemistry & Molecular Biology

A synthetic small molecule stalls pre-mRNA splicing by promoting an early-stage U2AF2-RNA complex

Rakesh Chatrikhi et al.

Summary: This study identifies a compound that enhances RNA binding by the U2AF2 subunit and inhibits splicing of representative substrates, effectively killing cancer cells by stalling spliceosome assembly. The results suggest that trapping early spliceosome assembly could be an effective pharmacological approach for manipulating pre-mRNA splicing.

CELL CHEMICAL BIOLOGY (2021)

Article Multidisciplinary Sciences

Regulated control of gene therapies by drug-induced splicing

Alex Mas Monteys et al.

Summary: A universal switch element has been developed for precise control of gene replacement or editing machinery after exposure to small molecules. This switch system, called X-on, allows controlled protein expression by adjusting drug dose, protein stability, and redosing. It offers an opportunity to refine and tailor gene therapies in humans due to its oral bioavailability and safety of the drugs used.

NATURE (2021)

Article Biochemistry & Molecular Biology

A novel class of inhibitors that target SRSF10 and promote p53-mediated cytotoxicity on human colorectal cancer cells

Muhammad Sohail et al.

Summary: Elevated expression of splicing regulator SRSF10 in metastatic colorectal cancer stimulates the production of pro-tumorigenic BCLAF1-L. Small molecules such as GPS167 and GPS192 have been found to decrease the production of BCLAF1-L and impact alternative splicing events in CRC cells through inhibiting CLK kinases, resulting in p53-dependent apoptosis. GPS167 reprograms the tumorigenic activity of SRSF10 in CRC cells while minimally affecting normal colonocytes.

NAR CANCER (2021)

Review Biotechnology & Applied Microbiology

Targeting mRNA processing as an anticancer strategy

Joana Desterro et al.

NATURE REVIEWS DRUG DISCOVERY (2020)

Article Biochemistry & Molecular Biology

Structural complementarity facilitates E7820-mediated degradation of RBM39 by DCAF15

Tyler B. Faust et al.

NATURE CHEMICAL BIOLOGY (2020)

Article Biochemistry & Molecular Biology

Splicing Kinetics and Coordination Revealed by Direct Nascent RNA Sequencing through Nanopores

Heather L. Drexler et al.

MOLECULAR CELL (2020)

Article Biochemistry & Molecular Biology

CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma

Nathan T. Ross et al.

NATURE CHEMICAL BIOLOGY (2020)

Review Oncology

Roles and mechanisms of alternative splicing in cancer - implications for care

Sophie C. Bonnal et al.

NATURE REVIEWS CLINICAL ONCOLOGY (2020)

Article Multidisciplinary Sciences

A large-scale binding and functional map of human RNA-binding proteins

Eric L. Van Nostrand et al.

NATURE (2020)

Review Biotechnology & Applied Microbiology

Advances in oligonucleotide drug delivery

Thomas C. Roberts et al.

NATURE REVIEWS DRUG DISCOVERY (2020)

Article Multidisciplinary Sciences

Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression

Kian Huat Lim et al.

NATURE COMMUNICATIONS (2020)

Article Multidisciplinary Sciences

Identification of phenothiazine derivatives as UHM-binding inhibitors of early spliceosome assembly

Pravin Kumar Ankush Jagtap et al.

NATURE COMMUNICATIONS (2020)

Article Cell Biology

Structural Insights into Nuclear p e-mRNA Splicing in Higher Eukaryotes

Berthold Kastner et al.

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY (2019)

Article Cell Biology

Structural Basis of Nuclear pre-mRNA Splicing: Lessons from Yeast

Clemens Plaschka et al.

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY (2019)

Review Genetics & Heredity

Alternative cleavage and polyadenylation in health and disease

Andreas J. Gruber et al.

NATURE REVIEWS GENETICS (2019)

Article Multidisciplinary Sciences

Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma

Shatha AbuHammad et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2019)

Article Multidisciplinary Sciences

Spliceosomal disruption of the non-canonical BAF complex in cancer

Daichi Inoue et al.

NATURE (2019)

Article Biochemistry & Molecular Biology

Structural basis of a small molecule targeting RNA for a specific splicing correction

Sebastien Campagne et al.

NATURE CHEMICAL BIOLOGY (2019)

Article Biochemistry & Molecular Biology

PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia

Aliaksandra Radzisheuskaya et al.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2019)

Article Medicine, General & Internal

Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease

J. Kim et al.

NEW ENGLAND JOURNAL OF MEDICINE (2019)

Article Biochemistry & Molecular Biology

Exon-Mediated Activation of Transcription Starts

Ana Fiszbein et al.

Article Biochemistry & Molecular Biology

Mechanistic insights into mRNA 3′-end processing

Ananthanarayanan Kumar et al.

CURRENT OPINION IN STRUCTURAL BIOLOGY (2019)

Article Cell Biology

Molecular Mechanisms of pre-mRNA Splicing through Structural Biology of the Spliceosome

Chuangye Yan et al.

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY (2019)

Article Oncology

Comprehensive Characterization of Alternative Polyadenylation in Human Cancer

Yu Xiang et al.

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE (2018)

Review Clinical Neurology

Antisense oligonucleotides: the next frontier for treatment of neurological disorders

Carlo Rinaldi et al.

NATURE REVIEWS NEUROLOGY (2018)

Article Oncology

Comprehensive Characterization of Alternative Polyadenylation in Human Cancer

Yu Xiang et al.

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE (2018)

Review Cell Biology

Targeting splicing abnormalities in cancer

Anant A. Agrawal et al.

CURRENT OPINION IN GENETICS & DEVELOPMENT (2018)

Article Medicine, Research & Experimental

Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability

Kenichi Iwai et al.

EMBO MOLECULAR MEDICINE (2018)

Article Biochemistry & Molecular Biology

Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds

Constantin Cretu et al.

MOLECULAR CELL (2018)

Article Multidisciplinary Sciences

Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype

Anne Walter et al.

PLOS ONE (2018)

Article Multidisciplinary Sciences

Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia

Shih-Han Lee et al.

NATURE (2018)

Article Biotechnology & Applied Microbiology

Intron retention is a source o neoepitopes in cancer

Alicia C. Smart et al.

NATURE BIOTECHNOLOGY (2018)

Article Multidisciplinary Sciences

SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4

Konstantinos Tzelepis et al.

NATURE COMMUNICATIONS (2018)

Article Biochemistry & Molecular Biology

SRPKIN-1: A Covalent SRPK1/2 Inhibitor that Potently Converts VEGF from Pro-angiogenic to Anti-angiogenic Isoform

John M. Hatcher et al.

CELL CHEMICAL BIOLOGY (2018)

Article Biotechnology & Applied Microbiology

Discovery of physiological and cancer-related regulators of 3′ UTR processing with KAPAC

Andreas J. Gruber et al.

GENOME BIOLOGY (2018)

Review Cell Biology

Alternative polyadenylation of mRNA precursors

Bin Tian et al.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2017)

Review Cell Biology

The roles of RNA processing in translating genotype to phenotype

Kassie S. Manning et al.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2017)

Article Oncology

U1 Adaptors Suppress the KRAS-MYC Oncogenic Axis in Human Pancreatic Cancer Xenografts

Ashley T. Tsang et al.

MOLECULAR CANCER THERAPEUTICS (2017)

Review Biochemistry & Molecular Biology

Arginine Methylation: The Coming of Age

Romeo S. Blanc et al.

MOLECULAR CELL (2017)

Article Biochemistry & Molecular Biology

Selective degradation of splicing factor CAPERα by anticancer sulfonamides

Taisuke Uehara et al.

NATURE CHEMICAL BIOLOGY (2017)

Article Genetics & Heredity

Pathogenic variants that alter protein code often disrupt splicing

Rachel Soemedi et al.

NATURE GENETICS (2017)

Review Cell Biology

Splicing and transcription touch base: co-transcriptional spliceosome assembly and function

Lydia Herzel et al.

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2017)

Review Cell Biology

Mechanistic insights into precursor messenger RNA splicing by the spliceosome

Yigong Shi

NATURE REVIEWS MOLECULAR CELL BIOLOGY (2017)

Article Biochemistry & Molecular Biology

U1 snRNP telescripting regulates a size-function-stratified human genome

Jung-Min Oh et al.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2017)

Article Medicine, General & Internal

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

R. S. Finkel et al.

NEW ENGLAND JOURNAL OF MEDICINE (2017)

Article Multidisciplinary Sciences

Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers

Manaswini Sivaramakrishnan et al.

NATURE COMMUNICATIONS (2017)

Article Multidisciplinary Sciences

CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor

Tyler Funnell et al.

NATURE COMMUNICATIONS (2017)

Article Multidisciplinary Sciences

Splicing modulators act at the branch point adenosine binding pocket defined by the PHF5A-SF3b complex

Teng Teng et al.

NATURE COMMUNICATIONS (2017)

Article Biochemistry & Molecular Biology

U1 snRNP telescripting regulates a size-function-stratified human genome

Jung-Min Oh et al.

NATURE STRUCTURAL & MOLECULAR BIOLOGY (2017)

Review Biochemistry & Molecular Biology

Development of Exon Skipping Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues

Annemieke Aartsma-Rus et al.

NUCLEIC ACID THERAPEUTICS (2017)

Article Biochemistry & Molecular Biology

Development of Potent, Selective SRPK1 Inhibitors as Potential Topical Therapeutics for Neovascular Eye Disease

Jennifer Batson et al.

ACS CHEMICAL BIOLOGY (2017)

Article Biochemistry & Molecular Biology

Coordination of RNA Polymerase II Pausing and 3 ' End Processing Factor Recruitment with Alternative Polyadenylation

Becky Fusby et al.

MOLECULAR AND CELLULAR BIOLOGY (2016)

Review Genetics & Heredity

RNA mis-splicing in disease

Marina M. Scotti et al.

NATURE REVIEWS GENETICS (2016)

Article Chemistry, Medicinal

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666

Kenneth W. Duncan et al.

ACS MEDICINAL CHEMISTRY LETTERS (2016)

Article Biochemistry & Molecular Biology

mRNA capping: biological functions and applications

Anand Ramanathan et al.

NUCLEIC ACIDS RESEARCH (2016)

Article Multidisciplinary Sciences

The spliceosome is a therapeutic vulnerability in MYC-driven cancer

Tiffany Y. -T. Hsu et al.

NATURE (2015)

Article Biochemistry & Molecular Biology

SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice

James Palacino et al.

NATURE CHEMICAL BIOLOGY (2015)

Article Biochemistry & Molecular Biology

A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models

Elayne Chan-Penebre et al.

NATURE CHEMICAL BIOLOGY (2015)

Article Multidisciplinary Sciences

Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia

Mayumi Yoshida et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2015)

Article Multidisciplinary Sciences

The human splicing code reveals new insights into the genetic determinants of disease

Hui Y. Xiong et al.

SCIENCE (2015)

Article Oncology

Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma

M. V. Gammons et al.

BRITISH JOURNAL OF CANCER (2014)

Article Biochemistry & Molecular Biology

Widespread intron retention in mammals functionally tunes transcriptomes

Ulrich Braunschweig et al.

GENOME RESEARCH (2014)

Article Biochemistry & Molecular Biology

ClinVar: public archive of relationships among sequence variation and human phenotype

Melissa J. Landrum et al.

NUCLEIC ACIDS RESEARCH (2014)

Article Multidisciplinary Sciences

SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

Nikolai A. Naryshkin et al.

SCIENCE (2014)

Article Clinical Neurology

Eteplirsen for the Treatment of Duchenne Muscular Dystrophy

Jerry R. Mendell et al.

ANNALS OF NEUROLOGY (2013)

Article Biochemistry & Molecular Biology

U1 snRNP Determines mRNA Length and Regulates Isoform Expression

Michael G. Berg et al.

Article Biochemistry & Molecular Biology

A quantitative atlas of polyadenylation in five mammals

Adnan Derti et al.

GENOME RESEARCH (2012)

Article Multidisciplinary Sciences

Landscape of transcription in human cells

Sarah Djebali et al.

NATURE (2012)

Article Medicine, General & Internal

Systemic Administration of PRO051 in Duchenne's Muscular Dystrophy

Nathalie M. Goemans et al.

NEW ENGLAND JOURNAL OF MEDICINE (2011)

Article Pediatrics

Kinetin Improves IKBKAP mRNA Splicing in Patients With Familial Dysautonomia

Felicia B. Axelrod et al.

PEDIATRIC RESEARCH (2011)

Article Cell Biology

Antisense Oligonucleotides Delivered to the Mouse CNS Ameliorate Symptoms of Severe Spinal Muscular Atrophy

Marco A. Passini et al.

SCIENCE TRANSLATIONAL MEDICINE (2011)

Article Multidisciplinary Sciences

U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation

Daisuke Kaida et al.

NATURE (2010)

Article Multidisciplinary Sciences

Deciphering the splicing code

Yoseph Barash et al.

NATURE (2010)

Article Multidisciplinary Sciences

Alternative isoform regulation in human tissue transcriptomes

Eric T. Wang et al.

NATURE (2008)

Article Genetics & Heredity

Genome-wide analysis of transcript isoform variation in humans

Tony Kwan et al.

NATURE GENETICS (2008)

Article Biochemistry & Molecular Biology

Rescue of a human mRNA splicing defect by the plant cytokinin kinetin

SA Slaugenhaupt et al.

HUMAN MOLECULAR GENETICS (2004)

Article Genetics & Heredity

A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy

T Kashima et al.

NATURE GENETICS (2003)

Article Biochemistry & Molecular Biology

Functional coupling of capping and transcription of mRNA

S Moteki et al.

MOLECULAR CELL (2002)