Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer
<p>Mechanisms of non-canonical splicing. (<b>A</b>) Pre-mRNAs circularization can be promoted by inverted Alu repeats- or RBPs dimerization-mediated base-pairing between upstream and downstream introns flanking circulating exons. (<b>B</b>) Inclusion of microexons (µ) is positively regulated by RBPs, such as SRRM4, RNPS1 and SRSF1, which favour spliceosome assembly on splice sites. (<b>C</b>) Two individual pre-mRNAs transcribed from the same gene can be spliced leading to an mRNA with an exon duplication (intragenic trans-splicing). Moreover, transcripts from different genes can be spliced to generate a chimeric RNA (intergenic trans-splicing). (<b>D</b>) During recursive splicing, long introns are removed in a two-step process mediated by the RS site, containing a 3′ splice site dinucleotide (AG) followed by a 5′ splice site dinucleotide (GU). In the first splicing reaction, the 3′ splice site of the RS site is used to remove the upstream part of the intron. The second splicing reaction uses the 5′ splice site of the RS site to remove the downstream part of the intron. Some recursively spliced introns contain an RS exon that is removed during the second step of the recursive splicing by usage of the new 5′ splice site generated by exon–RS exon junction.</p> "> Figure 2
<p>Functional role of non-canonical splicing in brain physiology. (<b>A</b>) CDRas1/ciRS-7 acted as a sponge for miR7 allowing for the expression of miR7-target genes. In CDRas1/ciRS-7 KO mice, miR7-target genes are downregulated resulting in defects in sensorimotor gating. (<b>B</b>) During brain development, downregulation of the splicing factor PTBP1 allowed for the neural-specific inclusion of microexon 5 in BAK1 mRNA. The inclusion of this microxon triggered NMD of Bak1 transcripts, leading to reduced expression of pro-apoptotic BAK1 protein and neuron survival. (<b>C</b>) The trans-spliced chimera generated by the RMST locus (tsRMST) guaranteed pluripotency of hESC by suppressing the expression of differentiation-related genes, such as GATA4, PAX6 and WNT5A, through the recruitment on their promoter of the transcription factor NANOG and PRC.</p> "> Figure 3
<p>Functional role of non-canonical splicing in brain tumours. (<b>A</b>) Upregulation of circ2082 in GBM cells impairs the regular miRNA processing by sequestering DICER in the nucleus of cancer cells. The resulting miRNA maturation machinery generates an aberrant miRNAome that drives tumorigenesis. (<b>B</b>) Reduced expression of the main regulator of neuronal microexons SRRM4 is associated with aggressive GBM. Several pieces of evidence across different tumours links the abnormal microexons’ splicing with enhanced proliferation and mitotic index. (<b>C</b>) In neuroblastoma cells (NB), the differentiation program, involving the complex BAG2/HSC70 on microtubules, is impaired by a trans-splicing event between the 3′ UTR of ZNF451 mRNA and the second exon of BAG2 mRNA, which generates a fusion transcript encoding a truncated BAG2 protein (ΔBAG2). ΔBAG2 is unable to bind HSC70 and subsequently unable to promote the degradation of the phosphorylated form of TAU.</p> ">
Abstract
:1. Introduction
2. Mechanisms of Canonical Splicing: Splicing and Alternative Splicing
2.1. Molecular Mechanisms Underlying Splicing Catalysis
2.2. Alternative Splicing
2.3. Regulation of Alternative Splicing
3. Mechanisms of Non-Canonical Splicing
3.1. Back-Splicing and Alternative Back-Splicing
3.1.1. Molecular Mechanisms Underlying circRNAs Biogenesis
3.1.2. Cis-Acting Elements and Trans-Acting Factors Involved in circRNAs Biogenesis
3.1.3. The Complex Crosstalk between Canonical Splicing and Back-Splicing
3.1.4. Cellular Functions of circRNAs
3.2. Splicing of Microexons
3.3. Trans-Splicing
3.3.1. Molecular Mechanisms Underlying Chimeric RNAs Biogenesis
3.3.2. Examples of Chimeric RNAs in Humans
3.4. Recursive Splicing
4. Impact of Non-Canonical Splicing in Brain Physiology
4.1. CircRNAs in Brain Physiology
4.2. Splicing of Microexons in Brain Physiology
4.3. Trans-Splicing in Brain Physiology
4.4. Recursive Splicing in Brain Physiology
5. Impact of Non-Canonical Splicing in Brain Tumours
5.1. circRNAs in Brain Tumours
5.1.1. CircRNAs in Gliomas
5.1.2. CircRNAs in Medulloblastoma
5.2. Splicing of Microexons in Brain Tumors
5.3. Trans-Splicing in Brain Tumors
6. Therapeutic Applications of Non-Canonical Splicing
7. Concluding Remarks
Author Contributions
Funding
Conflicts of Interest
References
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circRNAs | miRNAs | Dysregulation | Downstream Genes and Signaling Pathway Affected | Phenotype | Refs. |
---|---|---|---|---|---|
ciRS-7 | miR-7 | down | UBE2A | Neuropsychiatric-like phenotype | [53,54,235] |
circNT5E | miR-422a | up | PI3K/AKT signaling | Proliferation, Invasion | [159] |
circ0046701 | miR-142-3p | up | ITGB8 | Proliferation, Invasion | [160] |
circHIPK3 | miR-654 | up | IGF2BP3 | Proliferation, Invasion | [55,161] |
circ0014359 | miR-153 | up | PI3K/AKT signaling | Proliferation, migration, Invasion, apoptosis | [164] |
circNFIX | miR-34a-5p | up | Notch signaling | Proliferation, migration, Invasion, apoptosis | [165] |
circSHKBP1 | miR-544a miR-379 | up | FOXP1/FOXP2/AGG1 PI3K/AKT and ERK signaling | Proliferation, migration, angiogenesis | [166] |
circ002136 | miR-138-5p | up | SOX13/SPON2 | Migration, invasion angiogenesis | [168] |
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Pitolli, C.; Marini, A.; Sette, C.; Pagliarini, V. Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer. Int. J. Mol. Sci. 2022, 23, 2811. https://doi.org/10.3390/ijms23052811
Pitolli C, Marini A, Sette C, Pagliarini V. Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer. International Journal of Molecular Sciences. 2022; 23(5):2811. https://doi.org/10.3390/ijms23052811
Chicago/Turabian StylePitolli, Consuelo, Alberto Marini, Claudio Sette, and Vittoria Pagliarini. 2022. "Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer" International Journal of Molecular Sciences 23, no. 5: 2811. https://doi.org/10.3390/ijms23052811