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Splicing factor mutations and cancer

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Recent advances in high‐throughput sequencing technologies have unexpectedly revealed that somatic mutations of splicing factor genes frequently occurred in several types of hematological malignancies, including myelodysplastic syndromes, other myeloid neoplasms, and chronic lymphocytic leukemia. Splicing factor mutations have also been reported in solid cancers such as breast and pancreatic cancers, uveal melanomas, and lung adenocarcinomas. These mutations were heterozygous and mainly affected U2AF1 (U2AF35), SRSF2 (SC35), SF3B1 (SF3B155 or SAP155), and ZRSR2 (URP), which are engaged in the initial steps of RNA splicing, including 3′ splice‐site recognition, and occur in a large mutually exclusive pattern, suggesting a common impact of these mutations on RNA splicing. In this study, splicing factor mutations in various types of cancers, their functional/biological effects, and their potential as therapeutic targets have been reviewed. WIREs RNA 2014, 5:445–459. doi: 10.1002/wrna.1222 This article is categorized under: RNA Processing > Splicing Mechanisms

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Pre‐messenger RNA (mRNA) and major spliceosomes. The U1, U2, U4/U6, and U5 small nuclear ribonucloproteins (snRNPs) are the main components of the major spliceosomes, and each snRNP comprises a small nuclear RNA (snRNA) and a varying number of associated proteins. Assembly of spliceosomes begins with binding of U1 snRNP to the 5′ splice site of introns. Subsequently, U2 snRNP interacts with the branch point sequence (BPS) (A complex) and U4/U6.U5 tri‐snRNPs are recruited to form the B complex. After release of U1 and U4 snRNP, activated B complexes perform the catalytic process of splicing (C complex). This is a two‐step process, involving stepwise assembly of spliceosomes as splicing proceeds. In the first step, the 5′ splice site is cleaved and the 5′ residue of the intron is linked to near the 3′ splice junction. In the second step, the 3′ splice site is cleaved, producing ligated exons and excised ‘lariat’ introns. Subsequently, mRNA is released with the associated protein (mRNP).
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Potential of splicing factor mutations as therapeutic targets (synthetic lethality). Cancer cells carrying splicing factor mutations (lower panel) are likely to have compromised pre‐messenger RNA (mRNA) splicing and could be more sensitive to spliceosome inhibitors than nonmutated cells (upper panel).
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A variety of splicing alterations observed in mutant U2AF1‐transduced HeLa cells. The U2AF1 S34F‐mutant allele globally induces a variety of abnormal RNA splicing events, including exon skipping, unspliced introns, altered splice‐site recognition, and altered exon usage.
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Reported mutations of splicing factor genes including U2AF1, SRSF2, ZRSR2, and SF3B1 in myelodysplasia. Mutations of U2AF1, SRSF2, and SF3B1 were clustered in several hot spots (S34 and Q157 of U2AF1; P95 of SRSF2; E622, R625, H662, K666, and K700 of SF3B1), suggesting gain‐of‐function natures of these mutations. In contrast, ZRSR2 mutations were widely distributed along the entire coding region and most were nonsense mutations or frameshift changes, or were involved in splicing donor or acceptor sites that caused either a premature truncation or a large structural change in the protein, leading to loss‐of‐function. Zn, zinc finger domain; UHM, U2AF homology motif domain; RRM, RNA recognition motif domain; HD, HEAT domain.
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Frequent splicing factor mutations in myelodysplasia. Most mutations affected the initial steps of pre‐messenger RNA (mRNA) splicing, including 5′ splice‐site recognition (LUC7L2) and 3′ splice‐site recognition (SF3B1, SRSF2, U2AF1, ZRSR2, U2AF2, SF3A1, and SF1; upper panel). These mutations are almost mutually exclusive, suggesting a common impact on RNA splicing in the pathogenesis of myelodysplasia. Distribution of mutations in eight spliceosome genes; sample diagnoses are indicated by colors (lower panel). W, Trp residues; RRM, RNA recognition motif; UHM, U2AF homology motif domain; RS domain, arginine–serine‐rich domain.
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