HNRNPA2B1 Is a Mediator of m6A-Dependent Nuclear RNA Processing Events

Summary

N⁶-methyladenosine (m⁶A) is the most abundant internal modification of messenger RNA. While the presence of m⁶A on transcripts can impact nuclear RNA fates, a reader of this mark that mediates processing of nuclear transcripts has not been identified. We find that the RNA-binding protein HNRNPA2B1 binds m⁶A-bearing RNAs in vivo and in vitro and its biochemical footprint matches the m⁶A consensus motif. HNRNPA2B1 directly binds a set of nuclear transcripts and elicits similar alternative splicing effects as the m⁶A writer METTL3. Moreover, HNRNPA2B1 binds to m⁶A marks in a subset of primary miRNA transcripts, interacts with the microRNA Microprocessor complex protein DGCR8, and promotes primary miRNA processing. Also, HNRNPA2B1 loss and METTL3 depletion cause similar processing defects for these pri-miRNA precursors. We propose HNRNPA2B1 to be a nuclear reader of the m⁶A mark and to mediate, in part, this mark's effects on primary microRNA processing and alternative splicing.

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