Abstract
Simple SummaryThe spliceosome ribonucleoprotein complex catalyzes the removal of introns and exons ligation, a fundamental post-transcriptional process that generates mature RNAs. Cancer-associated mutations in spliceosome components give rise to aberrant splice site selection and, therefore, the production of novel isoform variants that support tumorigenesis. In this review, we summarize the current research regarding cancer hotspot mutations identified in spliceosome components acting at the very first step of splicing, namely the U1 snRNA, SF3B1, and U2AF1.Splicing alterations have been widely documented in tumors where the proliferation and dissemination of cancer cells is supported by the expression of aberrant isoform variants. Splicing is catalyzed by the spliceosome, a ribonucleoprotein complex that orchestrates the complex process of intron removal and exon ligation. In recent years, recurrent hotspot mutations in the spliceosome components U1 snRNA, SF3B1, and U2AF1 have been identified across different tumor types. Such mutations in principle are highly detrimental for cells as all three spliceosome components are crucial for accurate splice site selection: the U1 snRNA is essential for 3′ splice site recognition, and SF3B1 and U2AF1 are important for 5′ splice site selection. Nonetheless, they appear to be selected to promote specific types of cancers. Here, we review the current molecular understanding of these mutations in cancer, focusing on how they influence splice site selection and impact on cancer development.
Highlights
Splicing is a fundamental process in gene expression regulation and is essential for maintaining accurate cellular homeostasis, fitness, and fate
Intron removal relies on three pre-mRNA consensus sequences that are recognized by different spliceosome components: (i) the 50 and 30 splice sites, located at the 50 and 30 ends of the intron, (ii) the branch point sequence (BPS), located between 18 and 40 nucleotides upstream of the 30 splice site, and iii) the polypyrimidine tract (PPT), located between the BPS and the 30 splice site (Figure 1A)
In the case of adolescent patients presenting a mutation in sonic hedgehog (SHH), the U1 small nuclear RNAs (snRNAs) mutation was associated with high risk of relapse
Summary
Splicing is a fundamental process in gene expression regulation and is essential for maintaining accurate cellular homeostasis, fitness, and fate. The spliceosome undergoes a series of conformational changes that are mainly represented by base pairings occurring between pre-mRNA and snRNAs [1,3], [1,3], supported by DExD/H-type. In the complex A, the interaction between U1 and U2 snRNPs brings the two splice sites close to each other, followed by the recruitment of the preassembled U4-U6-U5 tri-snRNP, forming the pre-catalytic spliceosome or complex B This latter undergoes conformational and compositional rearrangements with the displacement of U1 and U4 snRNPs, determining the transition toward the complex Bact (activated) (Figure 1B). Three specific components of complex A have recently gained attention as they are recurrently mutated in various cancer types and affect the very first step in the splicing cycle: the U1 snRNA, which is essential for 50 splice site recognition, the U2 snRNP component. We review the current knowledge about the genetic characteristics of U1 snRNA, SF3B1, and U2AF1 somatic mutations and the mechanism by which they influence splicing decision and, as a consequence, tumor development
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