학술논문
N6 -methyladenosine regulates the stability of RNA:DNA hybrids in human cells
Document Type
Original Paper
Author
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, Bjørn; Emes, Richard D.; Gackowski, Daniel; Corrêa, Jr, Ivan R.; Garcia-Perez, Jose L.; Klungland, Arne; Gromak, Natalia; Ruzov, Alexey
Source
Nature Genetics. 52(1):48-55
Subject
Language
English
ISSN
1061-4036
1546-1718
1546-1718
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 cells1–4 . Here we show that N6 -methyladenosine (m6 A) 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 m6 A-containing R-loops accumulate during G2 /M and are depleted at G0 /G1 phases of the cell cycle, and that the m6 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 γH2AX, a marker for DNA double-strand breaks, in mammalian cells. Our results suggest that m6 A regulates accumulation of R-loops, implying a role for this modification in safeguarding genomic stability.
N6 -methyladenosine (m6 A) is prevalent at RNA:DNA hybrids in human pluripotent stem cells. The m6 A reader YTHDF2 interacts with R-loop-enriched loci in dividing cells, and YTHDF2 loss leads to increased R-loop levels and accumulation of γH2AX.
N