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

被引：168

作者：

Abakir, Abdulkadir ^{[1
]}

Giles, Tom C. ^{[2
,3
]}

Cristini, Agnese ^{[4
]}

Foster, Jeremy M. ^{[5
]}

Dai, Nan ^{[5
]}

Starczak, Marta ^{[6
]}

Rubio-Roldan, Alejandro ^{[7
]}

Li, Miaomiao ^{[8
,9
]}

Eleftheriou, Maria ^{[1
]}

Crutchley, James ^{[1
]}

Flatt, Luke ^{[1
]}

Young, Lorraine ^{[1
]}

Gaffney, Daniel J. ^{[10
]}

Denning, Chris ^{[1
]}

Dalhus, Bjorn ^{[8
,11
]}

Emes, Richard D. ^{[2
,12
]}

Gackowski, Daniel ^{[6
]}

Correa, Ivan R., Jr. ^{[5
]}

Garcia-Perez, Jose L. ^{[7
,13
]}

Klungland, Arne ^{[8
,9
]}

Gromak, Natalia ^{[4
]}

Ruzov, Alexey ^{[1
]}

机构：

[1] Univ Nottingham, Dept Stem Cell Biol, Nottingham, England

[2] Univ Nottingham, Adv Data Anal Ctr, Loughborough, England

[3] Univ Nottingham, Digital Res Serv, Loughborough, England

[4] Univ Oxford, Sir William Dunn Sch Pathol, Oxford, England

[5] New England Biolabs Inc, Ipswich, MA USA

[6] Nicolaus Copernicus Univ Torun, Dept Clin Biochem, Bydgoszcz, Poland

[7] Univ Granada, GENYO, Andalusian Reg Govt, Ctr Genom & Oncol Res Pfizer, Granada, Spain

[8] Oslo Univ Hosp, Dept Microbiol, Oslo, Norway

[9] Univ Oslo, Dept Mol Med, Oslo, Norway

[10] Wellcome Sanger Inst, Cambridge, England

[11] Univ Oslo, Dept Med Biochem, Oslo, Norway

[12] Univ Nottingham, Sch Vet Med & Sci, Loughborough, England

[13] Univ Edinburgh, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland

来源：

NATURE GENETICS | 2020年 / 52卷 / 01期

基金：

英国医学研究理事会; 英国国家替代、减少和改良动物研究中心; 英国生物技术与生命科学研究理事会;

关键词：

R-LOOPS; DNA METHYLATION; REVEALS; REPLICATION; ACCURATE; SITES; WIDE;

D O I：

10.1038/s41588-019-0549-x

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

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 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.

引用

页码：48 / +

页数：28

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