RNA Binding Motif 5 (RBM5) in the CNS—Moving Beyond Cancer to Harness RNA Splicing to Mitigate the Consequences of Brain Injury

Abstract

Gene splicing modulates the potency of cell death effectors, alters neuropathological disease processes, influences neuronal recovery, but may also direct distinct mechanisms of secondary brain injury. Therapeutic targeting of RNA splicing is a promising avenue for next-generation CNS treatments. RNA-binding proteins (RBPs) regulate a variety of RNA species and are prime candidates in the hunt for druggable targets to manipulate and tailor gene-splicing responses in the brain. RBPs preferentially recognize unique consensus sequences in targeted mRNAs. Also, RBPs often contain multiple RNA-binding domains (RBDs)-each having a unique consensus sequence-suggesting the possibility that drugs could be developed to block individual functional domains, increasing the precision of RBP-targeting therapies. Empirical characterization of most RBPs is lacking and represents a major barrier to advance this emerging therapeutic area. There is a paucity of data on the role of RBPs in the brain including, identification of their unique mRNA targets, defining how CNS insults affect their levels and elucidating which RBPs (and individual domains within) to target to improve neurological outcomes. This review focuses on the state-of-the-art of the RBP tumor suppressor RNA binding motif 5 (RBM5) in the CNS. We discuss its potent pro-death roles in cancer, which motivated our interest to study it in the brain. We review recent studies showing that RBM5 levels are increased after CNS trauma and that it promotes neuronal death in vitro. Finally, we conclude with recent reports on the first set of RBM5 regulated genes identified in the intact brain, and discuss how those findings provide new clues germane to its potential function(s) in the CNS, and pose new questions on its therapeutic utility to mitigate CNS injury.

Long read sequencing reveals novel isoforms and insights into splicing regulation during cell state changes

“…The implicated genes include the histone deacetylase gene, HDAC4 , and RACGAP1 , which encodes Rac GTPase Activating Protein 1, a protein critical for axon morphogenesis [ 39 ]. We also identified RNA binding motif protein 5 ( RBM5 ), a ubiquitous splicing regulator [ 40 ], among the genes showing differential transcript usage. Upon differentiation, we observed a switch from a truncated, non-coding RBM5 isoform ENST00000474470 to the full-length coding isoform ENST00000347869 during differentiation for this splicing factor.…”

Long read sequencing reveals novel isoforms and insights into splicing regulation during cell state changes

“…We identified RNA binding motif protein 5 ( RBM5 ), a ubiquitous splicing regulator (Jackson & Kochanek 2020), among the genes showing differential transcript usage. Upon differentiation, we observed a switch from a noncoding to a coding transcript for this splicing factor (Fig.…”

“…The function of RBM5 in neurogenesis is poorly understood (Jackson & Kochanek 2020), although its roles in apoptosis and tumour suppression (Xu et al 2019; Zhang et al 2019; Sutherland et al 2010; Bechara et al 2013) and spermatogenesis (O’Bryan et al 2013) are well documented. We show a clear switch from a truncated, non-coding RBM5 isoform ENST00000474470 to the full-length coding isoform ENST00000347869 during differentiation (Fig.…”

“…These neurodevelopmental processes are defined by ordered switches in exon usage and expression across a spectrum of genes, controlled by a suite of highly specific RNA-binding proteins (RBPs) such as NOVA2 (Saito et al 2019), PTBP1 and PTBP2 (Boutz et al 2007;Linares et al 2015;Keppetipola et al 2012). A number of more ubiquitous RBPs may also help regulate these neuronal AS events, though which ones and what specific roles they play remain poorly understood (Jackson et al 2020;Gallego-Paez et al 2017).…”

Development of prognostic signature based on RNA binding proteins related genes analysis in clear cell renal cell carcinoma

“…In total, 1542 RBPs were identified by genome-wide sequencing and bioinformatics analysis, which represent approximately seven percent of all protein-coding genes [ 3 ]. These RBPs were demonstrated to modulate molecular functions and biological processes such as RNA turnover, splicing, localization, and protein translation [ 8 ]. Furthermore, dysregulation of RBPs has been found in various human cancers, suggesting that RBPs may be reliable early molecular markers and therapeutic targets [ 9 ].…”