MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510006, China.
The Center for Medical Research, The First People's Hospital of Nanning City, Nanning 530021, China.
Nucleic Acids Res. 2022 Nov 11;50(20):11619-11634. doi: 10.1093/nar/gkac1027.
Telomeric repeat-containing RNA (TERRA) is a type of long non-coding RNA transcribed from telomeres, and it forms R-loops by invasion into telomeric DNA. Since either an excessive or inadequate number of R-loops leads to telomere instability, the TERRA levels need to be delicately modulated. In this study, we found that m6A modification presents on the subtelomeric regions of TERRA and stabilizes it, and the loss of METTL3 impacts telomere stability. Mechanically, the m6A modification on TERRA is catalyzed by METTL3, recognized and stabilized by the m6A reader YTHDC1. Knockdown of either METTL3 or YTHDC1 enhances TERRA degradation. The m6A-modified TERRA forms R-loops and promotes homologous recombination which is essential for the alternative lengthening of telomeres (ALT) pathway in cancer cells. METTL3 depletion leads to R-loop reduction, telomere shortening and instability. Altogether, these findings reveal that METTL3 protects telomeres by catalyzing m6A modification on TERRA, indicating that inhibition or deletion of METTL3 is potentially a new avenue for ALT cancer therapy.
端粒重复 RNA（TERRA）是一种从端粒转录而来的长非编码 RNA，它通过侵入端粒 DNA 形成 R 环。由于过多或过少的 R 环都会导致端粒不稳定，因此需要精细调节 TERRA 水平。在这项研究中，我们发现 TERRA 的亚端粒区域存在 m6A 修饰，并使其稳定，METTL3 的缺失会影响端粒稳定性。在机制上，TERRA 上的 m6A 修饰由 METTL3 催化，被 m6A 阅读器 YTHDC1 识别和稳定。敲低 METTL3 或 YTHDC1 均可增强 TERRA 降解。m6A 修饰的 TERRA 形成 R 环并促进同源重组，这对癌细胞的端粒替代性延长（ALT）途径至关重要。METTL3 耗竭会导致 R 环减少、端粒缩短和不稳定。总之，这些发现表明 METTL3 通过催化 TERRA 上的 m6A 修饰来保护端粒，表明抑制或缺失 METTL3 可能是 ALT 癌症治疗的新途径。
