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Nucleic Acids Res. 2017 Jun 2;45(10):6051-6063. doi: 10.1093/nar/gkx141.

N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein.

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Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
Medical Scientist Training Program, University of Chicago, Chicago, IL 60637, USA.
The Alan Edwards Centre for Research on Pain, Department of Dentistry, McGill University, Montréal, Québec H3A 0G1, Canada.
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
Institute of Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.


N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNA (mRNA), and affects almost every stage of the mRNA life cycle. The YTH-domain proteins can specifically recognize m6A modification to control mRNA maturation, translation and decay. m6A can also alter RNA structures to affect RNA-protein interactions in cells. Here, we show that m6A increases the accessibility of its surrounding RNA sequence to bind heterogeneous nuclear ribonucleoprotein G (HNRNPG). Furthermore, HNRNPG binds m6A-methylated RNAs through its C-terminal low-complexity region, which self-assembles into large particles in vitro. The Arg-Gly-Gly repeats within the low-complexity region are required for binding to the RNA motif exposed by m6A methylation. We identified 13,191 m6A sites in the transcriptome that regulate RNA-HNRNPG interaction and thereby alter the expression and alternative splicing pattern of target mRNAs. Low-complexity regions are pervasive among mRNA binding proteins. Our results show that m6A-dependent RNA structural alterations can promote direct binding of m6A-modified RNAs to low-complexity regions in RNA binding proteins.

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