N⁶-methyladenosine (m⁶A) is an essential internal RNA modification that is critical for gene expression control in most organisms. Proteins with a YTH domain recognize m⁶A marks and are mediators of molecular functions like RNA splicing, mRNA decay, and translation control. Here we demonstrate that YTH domain-containing 2 (YTHDC2) is an m⁶A reader that is essential for male and female fertility in mice. High-throughput mapping of the m⁶A transcriptome and expression analysis in the Yhtdc2 mutant testes reveal an upregulation of m⁶A-enriched transcripts. Our biochemical studies indicate that YTHDC2 is an RNA-induced ATPase with a 3ʹ→5ʹ RNA helicase activity. Furthermore, YTHDC2 recruits the 5ʹ→3ʹ exoribonuclease XRN1 via Ankyrin repeats that are inserted in between the RecA modules of the RNA helicase domain. Our studies reveal a role for YTHDC2 in modulating the levels of m⁶A-modified germline transcripts to maintain a gene expression program that is conducive for progression through meiosis.

N ⁶ -甲基腺苷 (m ⁶ A) 是一种必不可少的内部 RNA 修饰，对于大多数生物体中的基因表达控制至关重要。具有 YTH 结构域的蛋白质可识别 m ⁶ A 标记，并且是 RNA 剪接、mRNA 衰变和翻译控制等分子功能的介质。在这里，我们证明了包含 YTH 域的 2 (YTHDC2) 是一个 m ⁶ A 阅读器，它对小鼠的雄性和雌性生育能力至关重要。Yhtdc2突变睾丸中m ⁶ A 转录组的高通量定位和表达分析揭示了 m ⁶的上调A-丰富的成绩单。我们的生化研究表明，YTHDC2 是一种 RNA 诱导的 ATP 酶，具有 3ʹ→5ʹ RNA 解旋酶活性。此外，YTHDC2 通过插入 RNA 解旋酶域的 RecA 模块之间的锚蛋白重复序列​​招募 5ʹ→3ʹ 外切核糖核酸酶 XRN1。我们的研究揭示了 YTHDC2 在调节 m ⁶ A 修饰的生殖系转录物水平以维持有利于通过减数分裂进展的基因表达程序中的作用。