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

NATURE GENETICS(2020)

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摘要
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. N6-methyladenosine (m6A) is prevalent at RNA:DNA hybrids in human pluripotent stem cells. The m6A reader YTHDF2 interacts with R-loop-enriched loci in dividing cells, and YTHDF2 loss leads to increased R-loop levels and accumulation of γH2AX.
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关键词
Epigenetics,Functional genomics,Gene regulation,Transcriptomics,Biomedicine,general,Human Genetics,Cancer Research,Agriculture,Gene Function,Animal Genetics and Genomics
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