期刊
NATURE GENETICS
卷 52, 期 1, 页码 48-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-019-0549-x
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资金
- BBSRC [BB/M012336/1, BB/N005759/1, BB/L013827/1] Funding Source: UKRI
- MRC [MR/J007870/1, 1792340, MR/M017354/1] Funding Source: UKRI
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 cells(1-4). Here we show that N-6-methyladenosine (m(6)A) modification, contributing to different aspects of messenger RNA metabolism(5,6), is detectable on the majority of RNA:DNA hybrids in human pluripotent stem cells. We demonstrate that m(6)A-containing R-loops accumulate during G(2)/M and are depleted at G(0)/G(1) phases of the cell cycle, and that the m(6)A 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 gamma H2AX, a marker for DNA double-strand breaks, in mammalian cells. Our results suggest that m(6)A regulates accumulation of R-loops, implying a role for this modification in safeguarding genomic stability. N-6-methyladenosine (m(6)A) is prevalent at RNA:DNA hybrids in human pluripotent stem cells. The m(6)A reader YTHDF2 interacts with R-loop-enriched loci in dividing cells, and YTHDF2 loss leads to increased R-loop levels and accumulation of gamma H2AX.
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