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Article
Interaction between MED12 and ΔNp63 activates basal identity in pancreatic ductal adenocarcinoma
The presence of basal lineage characteristics signifies hyperaggressive human adenocarcinomas of the breast, bladder and pancreas. However, the biochemical mechanisms that maintain this aberrant cell state are...
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Article
Open AccessSpecificity, synergy, and mechanisms of splice-modifying drugs
Drugs that target pre-mRNA splicing hold great therapeutic potential, but the quantitative understanding of how these drugs work is limited. Here we introduce mechanistically interpretable quantitative models ...
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Article
Open AccessRBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer
Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive local invasion and metastatic spread, leading to high lethality. Although driver gene mutations during PDA progression are conserved, no sp...
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Article
Open AccessGene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy
Low CFTR mRNA expression due to nonsense-mediated mRNA decay (NMD) is a major hurdle in develo** a therapy for cystic fibrosis (CF) caused by the W1282X mutation in the CFTR gene. CFTR-W1282X truncated protein ...
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Article
Open AccessAuthor Correction: Therapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia
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Article
Open AccessTherapeutic manipulation of IKBKAP mis-splicing with a small molecule to cure familial dysautonomia
Approximately half of genetic disease-associated mutations cause aberrant splicing. However, a widely applicable therapeutic strategy to splicing diseases is yet to be developed. Here, we analyze the mechanism...
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Article
SRSF1 mediates cytokine-induced impaired imatinib sensitivity in chronic myeloid leukemia
Patients with chronic myeloid leukemia (CML) who are treated with tyrosine kinase inhibitors (TKIs) experience significant heterogeneity regarding depth and speed of responses. Factors intrinsic and extrinsic ...
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Article
Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis
Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations ...
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Article
Open AccessBinding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers
Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing ...
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Article
Open AccessGlobal identification of hnRNP A1 binding sites for SSO-based splicing modulation
Many pathogenic genetic variants have been shown to disrupt mRNA splicing. Besides splice mutations in the well-conserved splice sites, mutations in splicing regulatory elements (SREs) may deregulate splicing ...
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Article
Antisense oligonucleotide–directed inhibition of nonsense-mediated mRNA decay
Antisense oligonucleotides target genetic disease via gene-specific inhibition of nonsense-mediated mRNA decay.
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Article
Open AccessThe spliceosome, a potential Achilles heel of MYC-driven tumors
Alterations in RNA splicing are frequent in human tumors. Two recent studies of lymphoma and breast cancer have identified components of the spliceosome — the core splicing machinery — that are essential for m...
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Article
Open AccessDifferential connectivity of splicing activators and repressors to the human spliceosome
During spliceosome assembly, protein-protein interactions (PPI) are sequentially formed and disrupted to accommodate the spatial requirements of pre-mRNA substrate recognition and catalysis. Splicing activator...
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Article
Splicing factor SRSF6 promotes hyperplasia of sensitized skin
A new study identifies the splicing factor SRSF6 as a proto-oncogene frequently overexpressed in human skin cancer. SRSF6-overexpressing mice develop skin hyperplasia and aberrant alternative splicing, with SR...
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Chapter and Conference Paper
Correction of RNA Splicing with Antisense Oligonucleotides as a Therapeutic Strategy for a Neurodegenerative Disease
Spinal muscular atrophy (SMA) is a severe genetic disease inherited in autosomal recessive fashion. It is the leading genetic cause of infant mortality. SMA is a neuromuscular disease, characterized by progres...
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Article
Open AccessA generalizable pre-clinical research approach for orphan disease therapy
With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At pr...
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Article
Synthetic oligonucleotides recruit ILF2/3 to RNA transcripts to modulate splicing
Antisense oligonucleotides (ASOs) are widely used to modulate gene expression through sequence-specific duplex formation with target RNAs. ASOs containing specific 2′-fluorine substitutions are shown to recrui...
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Article
RNA therapeutics: beyond RNA interference and antisense oligonucleotides
All RNA-targeted therapeutic technologies exploit oligonucleotides that bind to target RNA, but they differ in their mechanism of action and produce different ...
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Article
The splicing factor SRSF1 regulates apoptosis and proliferation to promote mammary epithelial cell transformation
The splicing factor SRSF1 is an oncoprotein that is upregulated in human tumors, including breast cancer tumors. New in vitro and in vivo analyses reveal SRSF1's ability to transform human mammary epithelial cell...
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Protocol
Antisense-Mediated Exon Inclusion
Exon skip** induced by gene mutations is a common mechanism responsible for many genetic diseases. A practical approach to correct the aberrant splicing of defective genes is to use antisense oligonucleotide...
