Key Points
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Genetic and functional data indicate that RNA splicing factors can act as oncoproteins as well as tumour suppressors.
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A subset of RNA splicing factors are recurrent targets of specific point mutations in cancer. Many other splicing factors exhibit dysregulated expression in cancer.
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In many cases, recurrent spliceosomal mutations alter splice site or exon recognition preferences to cause abnormal RNA splicing.
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Spliceosomal mutations are sufficient to impair myeloid differentiation in mouse models. In the case of serine/arginine-rich splicing factor 2 (SRSF2), impaired differentiation has been linked to a specific splicing change in a downstream gene (enhancer of zeste homologue 2 (EZH2)).
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Spliceosomal mutations may affect cellular processes, including epigenetic regulation, the DNA damage response and nonsense-mediated decay, in addition to regulation of RNA splicing.
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Small molecules that disrupt splicing catalysis and/or targeted correction of specific splicing changes may provide novel therapeutic opportunities for cancers bearing spliceosomal mutations.
Abstract
The recent genomic characterization of cancers has revealed recurrent somatic point mutations and copy number changes affecting genes encoding RNA splicing factors. Initial studies of these 'spliceosomal mutations' suggest that the proteins bearing these mutations exhibit altered splice site and/or exon recognition preferences relative to their wild-type counterparts, resulting in cancer-specific mis-splicing. Such changes in the splicing machinery may create novel vulnerabilities in cancer cells that can be therapeutically exploited using compounds that can influence the splicing process. Further studies to dissect the biochemical, genomic and biological effects of spliceosomal mutations are crucial for the development of cancer therapies targeted at these mutations.
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Acknowledgements
H.D. is supported by a grant from the US Department of Defense Breast Cancer Research Program (W81XWH-14-1-0044). E.K. is supported by the Worldwide Cancer Research Fund. R.K.B. and O.A.-W. are supported by grants from the Edward P. Evans Foundation, the Department of Defense Bone Marrow Failure Research Program (BM150092) and National Institutes of Health/National Heart, Lung and Blood Institute (NIH/NHLBI) (R01 HL128239). O.A.-W. is supported by an NIH K08 Clinical Investigator Award (1K08CA160647-01), a US Department of Defense Postdoctoral Fellow Award in Bone Marrow Failure Research (W81XWH-12-1-0041), the Starr Cancer Consortium (I8-A8-075), the Josie Robertson Investigator Program, a Damon Runyon Clinical Investigator Award with support from the Evans Foundation, the Mr William H. Goodwin and Mrs Alice Goodwin Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center. R.K.B. is supported by the Ellison Medical Foundation (AG-NS-1030-13) and NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK103854).
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Glossary
- Major spliceosome
-
A ribonucleoprotein complex consisting of five small nuclear RNAs (termed U1, U2, U4, U5 and U6), each in complex with a set of proteins to form small nuclear ribonucleoprotein complexes (snRNPs), that together are responsible for excision of most introns.
- Minor spliceosome
-
A ribonucleoprotein complex that catalyses splicing of a small subset of U12-type introns. The introns recognized by the minor spliceosome are typically defined by sequence elements different from those that define U2-type introns, which are recognized by the major spliceosome.
- Small nuclear ribonucleoprotein complexes
-
(snRNPs). These complexes assemble on pre-mRNA to catalyse splicing.
- U2AF complex
-
A heterodimeric protein complex consisting of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and U2AF2. U2AF2 and U2AF1 bind to the polypyrimidine tract and AG dinucleotide of the 3′ splice site to facilitate splice site recognition. Only a subset of AG-dependent 3′ splice sites require U2AF1 binding for efficient splice site recognition.
- Constitutive splice sites
-
Splice sites that are always recognized and used by the spliceosome. Similarly, constitutive exons are always included in the mature mRNA.
- Alternative splice sites
-
Splice sites that are variably recognized and used by the spliceosome. Similarly, alternative exons (also known as cassette or skipped exons) are sometimes, but not always, included in the mature mRNA. Recognition of alternative splice sites is frequently cell type specific and may rely upon the binding of additional trans-acting factors.
- Expressed sequence tag
-
(EST). Portions of cDNA sequences.
- Unannotated splicing
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Splicing events that have not been previously reported by published studies or genomic databases such as Ensembl, UCSC, Vega and RefSeq.
- ψ value
-
The percentage of all mRNAs transcribed from a gene that correspond to a particular isoform or contain a particular alternatively spliced sequence relative to all transcripts of the parent gene. For example, the ψ value for a cassette exon is the fraction of all mRNAs that contain the cassette exon. The ψ value is independent of gene expression and falls within the range 0–100%.
- Serine/arginine-rich proteins
-
(SR proteins). A family of splicing factors that frequently promote splicing, although their action is context dependent. Many of these proteins bind to pre-mRNA in a sequence-specific manner to activate splicing. Some members of the family are implicated in other cellular processes, including mRNA export and translation.
- Heterogeneous nuclear ribonucleoproteins
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(hnRNPs). Many members of this protein family are splicing factors, although they also participate in other diverse RNA metabolic processes. These proteins frequently repress splicing, although their actions are context dependent.
- Acute myeloid leukaemia
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A type of cancer characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells.
- Myelodysplastic syndromes
-
(MDS). A heterogeneous group of clonal disorders of haematopoiesis characterized by an impaired ability to generate mature blood cells as well as aberrant cell morphologies (termed dysplasia).
- Chronic lymphocytic leukaemia
-
(CLL). A type of cancer characterized by accumulation of aberrant mature-appearing B lymphocytes.
- SF3B1
-
A gene encoding a key component of the U2 small nuclear ribonucleoprotein complex (snRNP) that binds upstream of the branch point to facilitate 3′ splice site recognition. SF3B1 is probably required for the splicing of most introns and is the most commonly mutated splicing factor in cancer.
- SRSF2
-
A gene encoding a serine/arginine-rich protein (SR protein) that binds to specific exonic splicing enhancer motifs to promote recognition and inclusion of exons containing these motifs.
- ZRSR2
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A gene encoding a component of the minor spliceosome that contacts the 3′ splice site of specific U12-type introns to promote their excision.
- Synthetic lethality
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The situation in which two cellular perturbations (for example, two distinct mutations, or a mutation and a particular drug) result in cell death when combined whereas each perturbation alone does not.
- Stop codons
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UAA, UAG or UGA codons, signalling the end of translation. Also known as termination codons.
- Exonic splicing enhancer
-
A typically short sequence motif in pre-mRNA that is bound by a splicing factor to promote exon recognition and subsequent inclusion of the exon in the mature mRNA. Many serine/arginine-rich (SR) proteins bind exonic splicing enhancers to activate splicing.
- Secondary AML
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(sAML). Acute myeloid leukaemia that develops following a previous chronic myeloid malignancy such as a myelodysplastic syndrome.
- Cryptic 3′ splice sites
-
Potential 3′ splice sites that are not normally recognized by the spliceosome. By chance, introns and exons contain many AG dinucleotides that are not used as splice sites. Perturbations such as spliceosomal mutations can cause such 'decoy splice sites' to be incorrectly recognized as authentic splice sites.
- Chronic myelomonocytic leukaemia
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(CMML). A clonal disorder with features of both myelodysplastic and myeloproliferative syndromes in which there are too many monocytes in the blood.
- Poison exon
-
A cassette exon containing an in-frame premature stop codon. A premature stop codon lies upstream of the normal stop codon, resulting in premature termination of translation of the mRNA when it is included in a transcript. Poison exons can induce nonsense-mediated decay of the mRNA or production of a truncated protein.
- Nonsense-mediated decay
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(NMD). An RNA surveillance process that recognizes and degrades mRNAs containing premature stop codons, as well as other abnormal RNAs and a subset of normal coding transcripts. Splicing is closely linked to NMD, as exon–exon junctions are important components of NMD activation in human cells.
- RNA polymerase II pause release
-
The process by which RNA polymerase II that is paused (not actively transcribing) after the initiation of transcription is released, enabling transcriptional elongation.
- Frameshift
-
The disruption of an open reading frame by the insertion or deletion of nucleotide sequence whose length is not a multiple of three.
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Dvinge, H., Kim, E., Abdel-Wahab, O. et al. RNA splicing factors as oncoproteins and tumour suppressors. Nat Rev Cancer 16, 413–430 (2016). https://doi.org/10.1038/nrc.2016.51
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DOI: https://doi.org/10.1038/nrc.2016.51
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