Identification and Characterization of a Nuclear Export Pathway for GC-Rich RNAs in Mammalian Cells




Thomas, Anu

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Splicing promotes nuclear export of RNAs by recruiting export factors to nascent transcripts. Nevertheless, many intronless RNAs are efficiently exported to the cytoplasm through mechanisms that remain poorly characterized. To identify new RNA export factors, we performed a genome-wide CRISPR screen to investigate the mechanism of export of NORAD, an intronless cytoplasmic long noncoding RNA. This screen revealed an RNA binding protein, RBM33, that directs the nuclear export of NORAD and numerous other transcripts. RBM33 directly binds substrate transcripts and recruits components of the NXF1-dependent RNA export pathway. Interestingly, high GC-content, not intron number or splicing efficiency, emerged as the feature that specifies RBM33-dependent nuclear export. Accordingly, RBM33 directly binds GC-rich elements in target transcripts. Importantly, these targets are nuclear enriched in RBM33 deficient cells, thereby establishing the role of RBM33 as a hitherto unknown nuclear export factor. These results provide a broadly applicable approach for the genetic dissection of nuclear export mechanisms and reveal the existence of an alternative RNA export route for GC-rich transcripts, providing a mechanistic basis for the long-standing observation that GC-rich sequence composition boosts gene expression and cytoplasmic localization.

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