N6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells

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

Abstract

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. 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 cells1–4. 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.

Citation

Abakir, A., Giles, T. C., Cristini, A., Foster, J. M., Dai, N., Starczak, M., Rubio-Roldan, A., Li, M., Eleftheriou, M., Crutchley, J., Flatt, L., Young, L., Gaffney, D. J., Denning, C., Dalhus, B., Emes, R. D., Gackowski, D., Corrêa, I. R., Garcia-Perez, J. L., Klungland, A., …Ruzov, A. (2020). N6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells. Nature Genetics, 52(1), 48-55. https://doi.org/10.1038/s41588-019-0549-x

• Journal Article Type: Letter
• Acceptance Date: Nov 13, 2019
• Online Publication Date: Dec 16, 2019
• Publication Date: 2020-01
• Deposit Date: Jul 21, 2020
• Publicly Available Date: Jul 27, 2020
• Journal: Nature Genetics
• Print ISSN: 1061-4036
• Electronic ISSN: 1546-1718
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 52
• Issue: 1
• Pages: 48-55
• DOI: https://doi.org/10.1038/s41588-019-0549-x
• Keywords: Genetics
• Public URL: https://nottingham-repository.worktribe.com/output/3610528
• Publisher URL: https://www.nature.com/articles/s41588-019-0549-x