Alternative Splicing Mechanisms in Cancer Biology

Alternative splicing is a fundamental mechanism by which precursor messenger RNA (pre-mRNA) transcripts are variably processed to yield multiple mature mRNA isoforms from a single gene. This process is orchestrated by the spliceosome, a dynamic ribonucleoprotein complex, and regulated by a host of RNA-binding proteins (RBPs) that recognise cis-acting sequences such as splice sites, branchpoints and exonic/intronic enhancers or silencers. In normal cells, alternative splicing expands proteome complexity and regulates processes including differentiation, apoptosis and stress responses. In cancer, however, dysregulated splicing—through mutation of core spliceosome components, altered expression of RBPs or shifts in transcriptional and epigenetic landscapes—can generate isoforms that promote oncogenic signalling, evade apoptosis, facilitate invasion and enable therapeutic resistance. Aberrant splicing may also modulate untranslated regions, affecting mRNA stability and translation. Advances in high-throughput sequencing, long-read technologies and functional assays have unveiled the extent of splicing alterations in tumours, highlighting both widespread isoform switches and cancer-specific events. Understanding the molecular determinants of splicing dysregulation has uncovered novel biomarkers and paved the way for therapeutic strategies that target splicing factors, harness splice-switching oligonucleotides or exploit synthetic splicing modulators to restore normal isoform balance or selectively suppress pathogenic transcripts.

Research from Nature Portfolio

Recent studies have undertaken large-scale functional screens to define the capacity of hundreds of human RBPs to induce exon inclusion, revealing previously unrecognised splicing regulators and enabling the engineering of compact fusion proteins that direct precise isoform outcomes. This work provides new molecular tools for programmable splicing modulation in cancer contexts. Investigations into the homeostasis of U1 small nuclear ribonucleoprotein (snRNP) have demonstrated that limiting U1 availability leads to widespread premature cleavage and polyadenylation, mRNA shortening and enhanced migration and invasion of cancer cells in vitro, whereas U1 overexpression reverses these phenotypes, pointing to U1 as a potential therapeutic node. Foundational research on SF3B1 hotspot mutations has elucidated how mutant SF3B1 alters branchpoint recognition to promote usage of cryptic 3′ splice sites, thereby driving aberrant splicing patterns in malignancy and deepening mechanistic insight into spliceosomal change-of-function mutations in cancer.

Alternative Splicing Mechanisms in Cancer Biology publication trend

The graph below shows the total number of articles in alternative splicing mechanisms in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

Alternative splicing: The process by which different combinations of exons are joined or skipped to generate multiple mRNA transcripts from a single gene.

Spliceosome: A multi-component ribonucleoprotein complex that recognises splice sites and catalyses intron removal and exon ligation.

RNA-binding protein (RBP): A protein that interacts with RNA sequences or structures to regulate RNA processing, stability, transport or translation.

Branchpoint: A conserved adenine nucleotide within an intron that serves as the nucleophile for the first catalytic step of splicing.

Isoform: A distinct mRNA or protein variant arising from a single gene through alternative splicing or other RNA processing events.

References

1. Alternative splicing and related RNA binding proteins in human health and disease. Signal Transduction and Targeted Therapy (2024).
2. Sites of transcription initiation drive mRNA isoform selection. Cell (2023).
3. Large-scale evaluation of the ability of RNA-binding proteins to activate exon inclusion. Nature Biotechnology (2024).
4. U1 snRNP regulates cancer cell migration and invasion in vitro. Nature Communications (2020).
5. The Functional Impact of Alternative Splicing in Cancer. Cell Reports (2017).
6. Cancer-associated SF3B1 mutations affect alternative splicing by promoting alternative branchpoint usage. Nature Communications (2016).