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

Journal article : Letter

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.

Authors: Abakir, A; Giles, TC; Cristini, A; Foster, JM; Dai, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature Genetics
• Volume: 52
• Issue: 1
• Pages: 48–55
• Publication date: 2019-12-16
• Acceptance date: 2019-11-13
• DOI: 10.1038/s41588-019-0549-x
• EISSN: 1546-1718
• ISSN: 1061-4036
• Pmid: 31844323
• Language: English
• Keywords: FFR
• Subtype: Letter