Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan.
Graduate School of Integrated Science and Technology, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka 422-8529, Japan.
Nucleic Acids Res. 2022 Jan 11;50(1):449-457. doi: 10.1093/nar/gkab1211.
N6-methyladenosine (m6A) is an important epitranscriptomic chemical modification that is mainly catalyzed by the METTL3/METTL14 RNA methyltransferase heterodimer. Although m6A is found at the consensus sequence of 5'-DRACH-3' in various transcripts, the mechanism by which METTL3/METTL14 determines its target is unclear. This study aimed to clarify the RNA binding property of METTL3/METTL14. We found that the methyltransferase heterodimer itself has a binding preference for RNA G-quadruplex (rG4) structures, which are non-canonical four-stranded structures formed by G-rich sequences, via the METTL14 RGG repeats. Additionally, the methyltransferase heterodimer selectively methylated adenosines close to the rG4 sequences. These results suggest a possible process for direct recruitment of METTL3/METTL14 to specific methylation sites, especially near the G4-forming regions. This study is the first to report the RNA binding preference of the m6A writer complex for the rG4 structure and provides insights into the role of rG4 in epitranscriptomic regulation.
N6-甲基腺苷（m6A）是一种重要的转录后化学修饰，主要由 METTL3/METTL14 RNA 甲基转移酶异二聚体催化。尽管 m6A 在各种转录本的 5'-DRACH-3' 保守序列中被发现，但 METTL3/METTL14 确定其靶标的机制尚不清楚。本研究旨在阐明 METTL3/METTL14 的 RNA 结合特性。我们发现甲基转移酶异二聚体本身通过 METTL14 的 RGG 重复序列对富含 G 的序列形成的非经典四链结构 RNA 四链体（rG4）结构具有结合偏好，这是由 G 丰富序列形成的非经典四链结构。此外，甲基转移酶异二聚体选择性地甲基化靠近 rG4 序列的腺苷。这些结果表明了 METTL3/METTL14 直接招募到特定甲基化位点（特别是靠近 G4 形成区域）的可能过程。本研究首次报道了 m6A 书写复合物对 rG4 结构的 RNA 结合偏好，并为 rG4 在转录后调控中的作用提供了新的见解。
