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
Department of Biochemistry, University of Toronto, Toronto, Canada.
Centre for Computational Medicine, Hospital for Sick Children, Toronto, Canada.
Life Sci Alliance. 2024 Dec 3;8(2). doi: 10.26508/lsa.202403142. Print 2025 Feb.
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.
在人类中，含有完整5'剪接位点（5'SS）基序的错误加工的mRNA会被核滞留，并被聚腺苷酸外切体靶向复合物的组分ZFC3H1和U1 snRNP的组分U1-70K靶向降解。在酵母中，ZFC3H1的同源物Red1与含YTH结构域的蛋白Mmi1结合，并将某些RNA转录本靶向核仁进行核滞留和降解。在这里，我们表明，YTHDC1和YTHDC2这两种与N6-甲基腺苷（m6A）修饰的RNA结合的含YTH结构域的蛋白，与ZFC3H1和U1-70K相互作用，并且是具有完整5'SS基序的mRNA核滞留所必需的。m6A沉积的破坏会抑制这些转录本的核滞留及其在与核斑点相邻的富含YTHDC1的核仁中的积累。具有完整5'SS基序的内源性RNA，如内含子聚腺苷酸化转录本，往往在低水平上被m6A修饰。因此，m6A修饰作用于一种保守的质量控制机制，该机制将错误加工的mRNA靶向核滞留和降解。
