RBM25 is a global splicing factor promoting inclusion of alternatively spliced exons and is itself regulated by lysine mono-methylation
2017
In eukaryotes,
precursor mRNA(pre-mRNA)
splicingremoves non-coding intron sequences to produce mature mRNA. This removal is controlled in part by
RNA-binding proteinsthat regulate
alternative splicingdecisions through interactions with the
splicingmachinery. RNA binding motif protein 25 (RBM25) is a putative
splicing factorstrongly conserved across eukaryotic lineages. However, the role of RBM25 in global
splicingregulation and its cellular functions are unknown. Here we show that RBM25 is required for the viability of multiple
human cell lines, suggesting that it could play a key role in pre-mRNA
splicing. Indeed, transcriptome-wide analysis of
splicingevents demonstrated that RBM25 regulates a large fraction of
alternatively splicedexons throughout the human genome. Moreover, proteomic analysis indicated that RBM25 interacts with components of the early
spliceosomeand regulators of
alternative splicing. Previously, we identified an RBM25 species that is mono-methylated at lysine 77 (RBM25K77me1), and here we used quantitative mass spectrometry to show that RBM25K77me1 is abundant in multiple
human cell lines. We also identified a region of RBM25 spanning Lys-77 that binds with high affinity to serine- and arginine-rich
splicing factor2 (SRSF2), a crucial protein in exon definition, but only when Lys-77 is unmethylated. Together, our findings uncover a pivotal role for RBM25 as an essential regulator of
alternative splicingand reveal a new potential mechanism for regulation of pre-mRNA
splicingby lysine methylation of a
splicing factor.
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