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A number of compounds, derived from bacterial fermentation products, have been found to target subunits of the spliceosome and display anticancer properties. In this Review, Valcárcel and colleagues discuss the role of splicing in cancer and how insights into the mechanism of action of these bacterial compounds might lead to the development of novel antitumour drugs.

In this study, Juan-Mateu et al. discover microexons that modulate insulin secretion in the pancreas in response to glucose levels in beta cell lines and mouse islets. Human genetic variants modulating these islet microexons are associated with type 2 diabetes risk.

The spliceosome is best known for shepherding primary messenger RNA transcripts to maturity. This enzyme complex also contributes to the synthesis of an enzyme that maintains chromosome ends.

Diverse messenger RNAs, and thus proteins, can be generated from a single piece of DNA. A computational approach is helping to uncover complex combinatorial rules by which specific gene instructions are selected.

Regulated splicing of some influenza virus RNAs is necessary for the synthesis of various essential proteins. Processing of these transcripts is now found to occur in nuclear speckles, previously considered storage sites for cellular splicing factors.

Genotype–phenotype landscapes are an important characteristic for understanding the evolution of traits. Here the authors construct the local landscape for the alternative splicing of FAS/CD95 exon 6, revealing the regulation of splicing and the evolution of regulatory information between species.

The spliceosome, the ribonucleoprotein complex that removes introns from precursor messenger RNAs, is thought to undergo conformational changes between two alternative states to catalyze the two steps of the splicing reaction, a model that resembles ribosomal transfer RNA decoding. Following very different strategies, two papers provide new insights into how core components of the spliceosome and regulatory factors containing arginine/serine-rich domains with RNA chaperone activity can facilitate these conformational changes.

Targeting PML in acute promyelocytic leukaemia has changed the outcome of patients with this disease. Here, the authors demonstrated that PML is also a potential therapeutic target in breast cancer where it specifically regulates cancer initiating cells and tumour progression through the transcriptional regulation of SOX9.

A new study combines massively parallel assays, transcriptomics and biophysical modeling to provide a framework for analyzing the effects of compounds that modulate pre-mRNA splicing. The results lend important insights into the mechanisms of drug action and facilitate the design of splicing therapies.

mRNAs associated with differentiated cells are already detected in adult neural stem cells. Here the authors show how intron detention prevents their translation, solving conflicts in fate decisions while priming stem cells for timely differentiation.

The RNA binding protein RBM5 regulates alternative splicing of genes implicated in cancer. Here the authors show structural mechanisms how multiple RNA binding domains of RBM5 cooperate to recognize specific target RNA sequences.

Several families of natural compounds target core components of the pre-mRNA splicing machinery and display anti-tumor activity. Here the authors show that particular sequence features can be linked to drug response, and that drugs with very similar chemical structures display substantially different effects on splicing regulation.

Human spliceosome components Smu1 and RED regulate alternative splicing. Here the authors show that Smu1 and RED are also required for constitutive splicing of short introns.

Microexons play a crucial role in neural development and are evolutionarily conserved. Comparing microexons across bilaterians, the authors find a new protein ___domain responsible for the evolution of neural specificity of microexons.

Dinucleotide CA repeats of variable length in an intron of the human endothelial nitric oxide synthase gene act as regulatory signals for splicing of the gene's pre-mRNA. Repeat length–dependent binding of hnRNP L to the repeats provides an intriguing link between splicing efficiency, nitric oxide synthesis and cardiovascular disease.

Hundreds of mRNA binding proteins (mRBPs) have been described in mammalian cells. Here, the authors identify RBPs differentially regulated in melanoma, and show the RBP CELF1 controlling a distinct set of protumorigenic factors.

Spinocerebellar ataxia type 1 (SCA1) is an inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1. The expanded polyglutamine tract can affect the function of the ataxin1 protein in different ways, depending on the protein partners ataxin1 is associated with. This paper shows that polyglutamine expansion in one and the same protein can cause gain of function and loss of function toxicity at the same time.

Although splicing factors are altered in cancer through mutations and copy number variations, their exact role remains challenging to define. In this Roadmap, Anczukow, Thomas-Tikhonenko and colleagues explore recent advances in splicing biology and provide guidance on leveraging these insights to facilitate the clinical application of compounds that target or exploit aberrant splicing patterns in cancer.

Inhibition of histone and DNA methyltransferase activity enhances sensitivity to platinum-based and immunotherapy in a novel transgenic mouse model of metastatic bladder cancer.

CPEB1 is known to regulate cytoplasmic polyadenylation, and is now shown to have a second function in the nucleus; it associates with the cleavage and polyadenylation machinery, thereby promoting usage of an upstream poly(A) signal in many messenger RNAs, and affecting alternative splicing.

Chromatin influences transcription, but its effects on downstream processing have been less clear. Analyses of published high-throughput data examining nucleosomal positions in T cell and C. elegans genomes now indicates that intron-exon architecture is reflected in nucleosome occupancy.

Alternative splicing of pre-mRNAs is key for cellular function and underpins the aetiology of numerous diseases. Here, we review major advances in understanding the structures and functions of the splicing machinery and its regulation, and in harnessing this knowledge for the design of novel therapies.

RNA-binding proteins (RBPs) are critical effectors of gene expression, and their malfunction underlies many diseases. The authors review the role of RBPs in human genetic disorders, both Mendelian and somatic, discuss the molecular mechanisms of disease and highlight emerging therapeutic interventions that target RBPs.

Alternative splicing enables the regulated generation of multiple mRNA and protein products from a single gene. This Review outlines the splicing process and its alterations in cancer before highlighting related opportunities for the development of innovative therapeutic approaches.