N⁶-Methyladenosine (m⁶A), the most abundant internal mRNA modification, affects multiple steps in gene expression. Mechanistically, the binding of YTHDF2 to m⁶A on mRNAs elicits rapid mRNA degradation by recruiting several RNA degrading enzymes. Here, we show that N¹-methyladenosine (m¹A), another type of RNA modification, accelerates rapid m⁶A RNA degradation. We identify HRSP12 as an RNA-binding protein that recognizes m¹A. The binding of HRSP12 to m¹A promotes efficient interaction of YTHDF2 with m⁶A, consequently facilitating endoribonucleolytic cleavage via the RNase P/MRP complex. Transcriptome-wide analyses also reveal that mRNAs harboring both m¹A and m⁶A are downregulated in an HRSP12-dependent manner compared with mRNAs harboring m⁶A only. Accordingly, a subset of endogenous circular RNAs that harbor m⁶A and associate with YTHDF2 in an HRSP12-dependent manner is also subjected to m¹A-facilitated rapid degradation. Together, our observations provide compelling evidence for crosstalk between different RNA modifications.

N ⁶ -甲基腺苷 (m ⁶ A) 是最丰富的内部 mRNA 修饰，影响基因表达的多个步骤。从机制上讲，YTHDF2 与 m ⁶ A 在 mRNA 上的结合通过募集几种 RNA 降解酶引起快速 mRNA 降解。在这里，我们展示了另一种类型的 RNA 修饰N ¹ -甲基腺苷 (m ¹ A) 加速了 m ⁶ A RNA 的快速降解。我们将 HRSP12 鉴定为识别 m ¹ A 的 RNA 结合蛋白。HRSP12 与 m ¹ A 的结合促进了 YTHDF2 与 m ^{6的有效相互作用}A，因此通过 RNase P/MRP 复合物促进内切核糖核酸裂解。转录组范围的分析还表明，与仅含有 m ^{6 A 的 mRNA 相比，含有 m 1} A 和 m ⁶ A 的 mRNA 以 HRSP12 依赖性方式下调。^{因此，含有 m 6} A 并以 HRSP12 依赖性方式与 YTHDF2 结合的内源性环状 RNA 子集也受到 m ¹ A 促进的快速降解。总之，我们的观察结果为不同 RNA 修饰之间的串扰提供了令人信服的证据。