Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer

Abstract

The advance of experimental and computational techniques has allowed us to highlight the existence of numerous different mechanisms of RNA maturation, which have been so far unknown. Besides canonical splicing, consisting of the removal of introns from pre-mRNA molecules, non-canonical splicing events may occur to further increase the regulatory and coding potential of the human genome. Among these, splicing of microexons, recursive splicing and biogenesis of circular and chimeric RNAs through back-splicing and trans-splicing processes, respectively, all contribute to expanding the repertoire of RNA transcripts with newly acquired regulatory functions. Interestingly, these non-canonical splicing events seem to occur more frequently in the central nervous system, affecting neuronal development and differentiation programs with important implications on brain physiology. Coherently, dysregulation of non-canonical RNA processing events is associated with brain disorders, including brain tumours. Herein, we summarize the current knowledge on molecular and regulatory mechanisms underlying canonical and non-canonical splicing events with particular emphasis on cis-acting elements and trans-acting factors that all together orchestrate splicing catalysis reactions and decisions. Lastly, we review the impact of non-canonical splicing on brain physiology and pathology and how unconventional splicing mechanisms may be targeted or exploited for novel therapeutic strategies in cancer.

Unconventional protein secretion (UPS): role in important diseases

“…Various aspects occurring in neurodegenerative and other diseases are not entirely different from the UPS events occurring in cancer. Similarities of these processes with those concerning physiology of brain cells, have been reported recently [ 92 ]. On the other hand, properties of cancer revealed during the last decade have confirmed the coexistence of specific cells, now identified as cancer stem cells (CSCs), together with generally distributed mesenchymal stem cells (MSCs).…”

“…(Fig. 3 b) [ 30 , 92 ]. Interestingly, such results have been reported to occur under intracellular control by APhs and their inhibitors [ 26 , 31 ].…”

Non-canonical functions of spliceosome components in cancer progression

“…Moreover, depending on the context, the same protein can both inhibit or activate splicing, which provides fine regulation of this process [15,16]. Besides canonical splicing, splicing of microexons, recursive splicing and biogenesis of circular and chimeric RNAs through back-splicing and transsplicing processes are also taken place in cells often involving the same molecular players [17]. Such a diversity of splicing machinery makes it highly flexible to accurately regulate splicing outcomes in a cell type-and intron-specific manner [18].…”

Mammalian glial protrusion transcriptomes predict localization ofDrosophilaglial transcripts required for synaptic plasticity

“…These significant associations highlight the hypothesis that the many of the localized mRNAs at the periphery of glia are required for neuron-glia, glia-muscle or glia-glia communication, and localized mRNA processing and metabolism at the distal cytoplasm of glia. Such mechanisms could potentially include non-canonical mRNA processing that has been previously suggested to be involved in brain physiology and cancer (Pitolli et al ., 2022). Moreover, another group that is worth highlighting is the “innate immune system” which is also highly enriched, showing that the availability of gene lists like ours could extend beyond the nervous system context.…”