m1A and m6A modifications function cooperatively to facilitate rapid mRNA degradation. Boo et al.

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 either deadenylation via the CCR4-NOT complex or endoribonucleolytic cleavage via HRSP12 and RNase P/MRP. 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 to 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.

N6-甲基腺苷（N6-methyladenosine，m6A）是真核生物mRNA中最丰富的内部RNA修饰类型，可影响基因表达的多个环节。从分子机制来看，YTHDF2与mRNA上的m6A结合后，可通过CCR4-NOT复合物介导的脱腺苷酸化过程，或是经由HRSP12与RNase P/MRP复合物介导的核糖内切核酸酶切割，引发mRNA的快速降解。本研究证实，另一种RNA修饰——N1-甲基腺苷（N1-methyladenosine，m1A）可加速m6A修饰RNA的快速降解。我们鉴定出HRSP12是一种能够识别m1A的RNA结合蛋白；HRSP12与m1A的结合可促进YTHDF2与m6A的有效相互作用，进而通过RNase P/MRP复合物介导核糖内切核酸酶切割反应。全转录组水平分析显示，与仅携带m6A修饰的mRNA相比，同时携带m1A和m6A修饰的mRNA会以HRSP12依赖的方式发生表达下调。相应地，一类内源性环状RNA（circular RNAs）若携带m6A修饰，且以HRSP12依赖的方式与YTHDF2结合，同样会受到m1A介导的快速降解调控。综上，本研究结果为不同RNA修饰之间的交叉对话提供了确凿证据。