19), and Tra2β is implicated in the pathology of other diseases including spinal muscular atrophy 20, Alzheimer’s disease 21 and frontotemporal dementia and Parkinsonism linked to chromosome 17 (ref. In humans, Tra2β expression levels change in several cancers (reviewed by Best et al. Knockout experiments in mice show that Tra2β is essential for embryonic and brain development 15, 16, 17, 18.
Tra2 proteins are conserved across the animal kingdom, but separate gene paralogs encoding Tra2α and Tra2β proteins evolved early in vertebrate evolution 13, 14. First discovered in insects, Tra2 proteins form an essential component of the alternative splicing complex that controls fly sexual differentiation 11, 12. Transformer2 (Tra2) proteins are involved in splicing control 9, 10. Although RNA-binding proteins can regulate many transcripts in parallel, some splicing regulatory proteins preferentially engage with transcripts belonging to specific functional classes, including Nova proteins (synapse functions), Fox proteins (neuromuscular, cytoskeleton and EMT functions), PTB proteins (cytoskeleton functions) and T-STAR (synapse functions) 4, 5, 6, 7, 8. RNA binding proteins play a key role in transforming precursor RNAs into mRNAs. Human protein-coding genes each produce an average of three mRNA isoforms through alternative splicing, many of which are differentially regulated 3. Constitutive exons splice into all mRNAs transcribed from a gene, while alternative exons are sometimes included and sometimes skipped 2. This maturation includes the splicing of exons, which normally occurs with high fidelity to create functional mRNAs 1. Human genes encode long precursor messenger RNAs (mRNAs) that are extensively processed before nuclear export. We conclude Tra2 proteins jointly control constitutive and alternative splicing patterns via paralog compensation to control pathways essential to the maintenance of cell viability.
Dual Tra2 protein depletion reduces expression of full-length CHK1 protein, results in the accumulation of the DNA damage marker γH2AX and decreased cell viability. Target exons are enriched in genes associated with chromosome biology including CHEK1, which encodes a key DNA damage response protein. Here we find simultaneous-but not individual-depletion of Tra2α and Tra2β induces substantial shifts in splicing of endogenous Tra2β target exons, and that both constitutive and alternative target exons are under dual Tra2α–Tra2β control. While the RBPs transformer2 alpha (Tra2α) and Tra2β have both been implicated in the regulation of alternative splicing, their relative contributions to this process are not well understood. Do whatever possible to keep them on staff and work to help less efficient employees improve.Alternative splicing-the production of multiple messenger RNA isoforms from a single gene-is regulated in part by RNA binding proteins.
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