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bioRxiv · 10.1101/2023.06.20.545713

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

Lee, E. S.·Scalize de Olivera, L.·Jomphe, R. Y.·Ihn, S. S.·Smith, H. W.·Nabeel-Shah, S.·Pu, S.·Greenblatt, J. F.·Palazzo, A. F.
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Abstract

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.

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Lee, E. S., Scalize de Olivera, L., Jomphe, R. Y., Ihn, S. S., Smith, H. W., Nabeel-Shah, S., Pu, S., Greenblatt, J. F., Palazzo, A. F.. 2023-06-21. N-6-methyladenosine (m6A) Promotes the Nuclear Retention of mRNAs with Intact 5' Splice Site Motifs. https://doi.org/10.1101/2023.06.20.545713

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