Abstract
The Muscleblind (MBL) protein family is a deeply conserved family of RNA binding proteins that regulate alternative splicing, alternative polyadenylation, RNA stability and RNA localization. Their inactivation due to sequestration by expanded CUG repeats causes symptoms in the neuromuscular disease myotonic dystrophy. MBL zinc fingers are the most highly conserved portion of these proteins, and directly interact with RNA. We identified putative MBL homologs in Ciona intestinalis and Trichoplax adhaerens, and investigated their ability, as well as that of MBL homologs from human/mouse, fly and worm, to regulate alternative splicing. We found that all homologs can regulate alternative splicing in mouse cells, with some regulating over 100 events. The cis-elements through which each homolog exerts its splicing activities are likely to be highly similar to mammalian Muscleblind-like proteins (MBNLs), as suggested by motif analyses and the ability of expanded CUG repeats to inactivate homolog-mediated splicing. While regulation of specific target exons by MBL/MBNL has not been broadly conserved across these species, genes enriched for MBL/MBNL binding sites in their introns may play roles in cell adhesion, ion transport and axon guidance, among other biological pathways, suggesting a specific, conserved role for these proteins across a broad range of metazoan species.
Highlights
Splicing is a co- or post-transcriptional process in which the spliceosome catalyzes excision of introns, or non-coding regions, from a precursor RNA transcript while concomitantly joining exons, or coding regions
The 41 kD isoform of MBNL1 contains the linker region between both pairs of zinc fingers, lacks exon 5, which can control nuclear/cytoplasmic localization, and lacks exon 7, which has been proposed to contribute to MBNL1 dimerization [6]
Zinc-finger X1 in Ciona, Muscleblind D in Drosophila, Muscleblind-1a in Caenorhabditis and a hypothetical protein in Trichoplax were identified as the highest scoring homologs. We refer to these proteins as HsMBNL1, CiMBL, DmMBL, CeMBL and TaMBL for human, Ciona, Drosophila, Caenorhabditis and Trichoplax Muscleblind proteins, respectively
Summary
Splicing is a co- or post-transcriptional process in which the spliceosome catalyzes excision of introns, or non-coding regions, from a precursor RNA transcript while concomitantly joining exons, or coding regions This structure of exons and introns enables the generation of multiple mRNA isoforms from a single gene through the exclusion and inclusion of exons and introns, leading to multiple protein isoforms. Trans-acting protein factors can function as regulators of alternative splicing by interacting with specific sequences, or RNA secondary structures, termed splicing regulatory elements, within the RNA transcript to regulate spliceosome recruitment to or interaction with splice sites These regulators can act in a spatio-temporal and developmentally dependent manner to enhance or repress inclusion of alternative exons [1,2].
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