英国诺丁汉大学Alexey Ruzov、牛津大学Natalia Gromak，挪威奥斯陆大学Arne Klungland等研究人员合作发现N⁶-甲基腺苷调节人类细胞中RNA：DNA杂交环的稳定性。2019年12月16日，《自然—遗传学》在线发表了这项成果。

研究人员发现，N⁶-甲基腺苷（m⁶A）修饰影响着信使RNA代谢的不同方面，这在人类多能干细胞中大多数RNA：DNA杂交环上能够被检测到。研究人员证明，包含m⁶A的R-loops在G₂/M期间积累，并在细胞周期的G₀/G₁阶段被耗尽，并且m⁶A阅读器（YTHDF2）促进mRNA降解，YTHDF2分裂细胞中与富含R-loops的基因座相互作用。因此，YTHDF2敲除导致哺乳动物细胞中R-loops水平提高、细胞生长迟缓和γH2AX（DNA双链断裂的标志物）的积累。这些结果表明，m⁶A调节R-loops的积累，这暗示了这种修饰在维护基因组稳定性中的作用。

据悉，R-loops是由RNA：DNA杂交环与未配对的单链DNA形成的核酸结构，代表着哺乳动物细胞中基因组不稳定的来源。

附：英文原文

Title: N 6 -methyladenosine regulates the stability of RNA:DNA hybrids in human cells

Author: Abdulkadir Abakir, Tom C. Giles, Agnese Cristini, Jeremy M. Foster, Nan Dai, Marta Starczak, Alejandro Rubio-Roldan, Miaomiao Li, Maria Eleftheriou, James Crutchley, Luke Flatt, Lorraine Young, Daniel J. Gaffney, Chris Denning, Bjrn Dalhus, Richard D. Emes, Daniel Gackowski, Ivan R. Corra, Jose L. Garcia-Perez, Arne Klungland, Natalia Gromak, Alexey Ruzov

Issue&Volume: 2019-12-16

Abstract: R-loops are nucleic acid structures formed by an RNA:DNA hybrid and unpaired single-stranded DNA that represent a source of genomic instability in mammalian cells1,2,3,4. Here we show that N6-methyladenosine (m6A) modification, contributing to different aspects of messenger RNA metabolism5,6, is detectable on the majority of RNA:DNA hybrids in human pluripotent stem cells. We demonstrate that m6A-containing R-loops accumulate during G2/M and are depleted at G0/G1 phases of the cell cycle, and that the m6A reader promoting mRNA degradation, YTHDF2 (ref. 7), interacts with R-loop-enriched loci in dividing cells. Consequently, YTHDF2 knockout leads to increased R-loop levels, cell growth retardation and accumulation of γH2AX, a marker for DNA double-strand breaks, in mammalian cells. Our results suggest that m6A regulates accumulation of R-loops, implying a role for this modification in safeguarding genomic stability.

DOI: 10.1038/s41588-019-0549-x

Source: https://www.nature.com/articles/s41588-019-0549-x