N -6-methyladenosine (m6A) promotes the nuclear retention of mRNAs with intact 5' splice site motifs

• Published in: Life science alliance 2025-02, Vol.8 (2), p.e202403142
• Main Authors: Lee, Eliza S, Smith, Harrison W, Wang, Yifan E, Ihn, Sean Sj, Scalize de Oliveira, Leticia, Kejiou, Nevraj S, Liang, Yijing L, Nabeel-Shah, Syed, Jomphe, Robert Y, Pu, Shuye, Greenblatt, Jack F, Palazzo, Alexander F
• Format: Article
• Language: English
• Subjects: Adenosine - analogs & derivatives; Adenosine - metabolism; Cell Nucleus - metabolism; HeLa Cells; Humans; Nerve Tissue Proteins; RNA Splice Sites - genetics; RNA Splicing - genetics; RNA Splicing Factors - genetics; RNA Splicing Factors - metabolism; RNA Stability - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202403142

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 , the ZFC3H1 homolog, Red1, binds to the YTH domain-containing protein Mmi1 and targets 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 -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 poly-adenylated transcripts, tend to be m6A-modified at low levels. Thus, the m6A modification acts on a conserved quality control mechanism that targets misprocessed mRNAs for nuclear retention and decay.