N-6-methyladenosine (m6A) Promotes the Nuclear Retention of mRNAs with Intact 5' Splice Site Motifs

In humans, misprocessed mRNAs containing intact 5' Splice Site (5'SS) motifs are nuclear retained and targeted for decay by ZFC3H1, a component of the Poly(A) Exosome Targeting complex, and U1-70K, a component of the U1 snRNP. In S. pombe, the ZFC3H1 homolog, Red1, binds to the YTH-domain containing protein Mmi1 to target certain RNA transcripts to nuclear foci for nuclear retention and decay. Here we show that YTHDC1 and YTHDC2, two YTH domain-containing proteins that bind to N-6-methyladenosine (m6A) modified RNAs, interact with ZFC3H1 and U1-70K, and are required for the nuclear retention of mRNAs with intact 5'SS motifs. Disruption of m6A deposition inhibits both the nuclear retention of these transcripts and their accumulation in YTHDC1-enriched foci that are adjacent to nuclear speckles. Endogenous RNAs with intact 5'SS motifs, such as intronic polyadenylated transcripts, tend to be m6A-modified at low levels. Thus, m6A modification acts in a conserved quality control mechanism that targets misprocessed mRNAs for nuclear retention and decay.