Dual roles of N6-methyladenosine in R-loop regulation of gene transcription and genome stability

被引:0
作者
Li, Fangle [1 ,2 ,3 ]
Zhang, Feifan [1 ,2 ,3 ]
Li, Jie [1 ,2 ]
Zhang, Yu [1 ,2 ]
Gong, Wenxuan [1 ,2 ]
Zhang, Yawei [1 ,2 ]
Liu, Mengxia [1 ,2 ]
Ren, Jie [1 ,2 ,3 ]
Han, Dali [1 ,2 ,3 ]
机构
[1] China Natl Ctr Bioinformat, Beijing 100101, Peoples R China
[2] Chinese Acad Sci, Beijing Inst Genom, State Key Lab RNA Innovat Sci & Engn, Beijing 100101, Peoples R China
[3] Univ Chinese Acad Sci, Coll Future Technol, Sino Danish Coll, Beijing 100049, Peoples R China
来源
SCIENCE CHINA-LIFE SCIENCES | 2025年
基金
中国国家自然科学基金; 北京市自然科学基金;
关键词
N(6)-methyladenosine; R-loop; DNA damage; transcriptional readthrough; genome stability; MESSENGER-RNA; DNA-DAMAGE; READ-THROUGH; METHYLATION; EXPRESSION; BINDING; PROTEIN; RECOMBINATION; TRANSLATION; IMPAIRMENT;
D O I
10.1007/s11427-024-2947-6
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
N6-methyladenosine (m6A) in RNA within R-loops plays pivotal roles in transcription regulation and genome stability. However, the precise impacts and distinct mechanisms of m6A on both regulatory and aberrant R-loops remain poorly understood. Here, we reveal that METTL3, the nuclear m6A writer, ensures genome integrity by differentially modulating R-loops in a position- and length-dependent manner. In mouse embryonic stem cells (mESCs), Mettl3 depletion results in impaired cell proliferation and increased cell death due to excessive DNA damage. Notably, Mettl3 knockout reduces the overall abundance of R-loops, with a decrease in broad R-loops and an increase in sharp R-loops. R-loops are diminished near transcription end sites (TESs), leading to transcriptional readthrough of genes with m6A-modified transcripts and potentially contributing to genome instability. Conversely, increased sharp R-loops located in the antisense orientation relative to gene transcription are associated with DNA damage hotspots. These findings unveil a dual regulatory mechanism in which METTL3-m6A orchestrates transcription fidelity and genome stability through distinct R-loop-dependent manners.
引用
收藏
页数:13
相关论文
共 92 条
[1]   A model for a dual function of N6-methyladenosine in R-loop regulation [J].
Abakir, Abdulkadir ;
Ruzov, Alexey .
NATURE GENETICS, 2024, 56 (10) :1995-1998
[2]   N6-methyladenosine regulates the stability of RNA:DNA hybrids in human cells [J].
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, Bjorn ;
Emes, Richard D. ;
Gackowski, Daniel ;
Correa, Ivan R., Jr. ;
Garcia-Perez, Jose L. ;
Klungland, Arne ;
Gromak, Natalia ;
Ruzov, Alexey .
NATURE GENETICS, 2020, 52 (01) :48-+
[3]  
Andersson-Rolf A, 2017, NAT METHODS, V14, P287, DOI [10.1038/NMETH.4156, 10.1038/nmeth.4156]
[4]   RNaseH1 regulates TERRA-telomeric DNA hybrids and telomere maintenance in ALT tumour cells [J].
Arora, Rajika ;
Lee, Yongwoo ;
Wischnewski, Harry ;
Brun, Catherine M. ;
Schwarz, Tobias ;
Azzalin, Claus M. .
NATURE COMMUNICATIONS, 2014, 5
[5]   Small-Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer [J].
Bedi, Rajiv K. ;
Huang Danzhi ;
Eberle, Stefanie A. ;
Wiedmer, Lars ;
Sledz, Pawel ;
Caflisch, Amedeo .
CHEMMEDCHEM, 2020, 15 (09) :744-748
[6]  
Bokar JA, 1997, RNA, V3, P1233
[7]   Head-to-head antisense transcription and R-loop formation promotes transcriptional activation [J].
Boque-Sastre, Raquel ;
Soler, Marta ;
Oliveira-Mateos, Cristina ;
Portela, Anna ;
Moutinho, Catia ;
Sayols, Sergi ;
Villanueva, Alberto ;
Esteller, Manel ;
Guil, Sonia .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2015, 112 (18) :5785-5790
[8]   RNA-modifying proteins as anticancer drug targets [J].
Boriack-Sjodin, P. Ann ;
Ribich, Scott ;
Copeland, Robert A. .
NATURE REVIEWS DRUG DISCOVERY, 2018, 17 (06) :435-453
[9]   Biological roles of adenine methylation in RNA [J].
Boulias, Konstantinos ;
Greer, Eric Lieberman .
NATURE REVIEWS GENETICS, 2023, 24 (03) :143-160
[10]   APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition [J].
Buisson, Remi ;
Lawrence, Michael S. ;
Benes, Cyril H. ;
Zou, Lee .
CANCER RESEARCH, 2017, 77 (17) :4567-4578