한빛사논문
Hyun Je Kang1,†, Na Young Cheon1,†, Hyun Park1, Gyu Won Jeong1, Byeong Jin Ye1, Eun Jin Yoo1, Jun Ho Lee1, Jin-Hoe Hur2, Eun-A Lee3, Hongtae Kim1,3, Kyoo-young Lee3, Soo Youn Choi, Whaseon Lee-Kwon, Kyungjae Myung1,3,*, Ja Yil Lee1,3,* and Hyug Moo Kwon1,*
1Department of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea,
2UNIST-Optical Biomed Imaging Center (UOBC), Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea and
3Center for Genomic Integrity, Institute for Basic Science, Ulsan 44919, Republic of Korea
*To whom correspondence should be addressed.
†The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
Abstract
R-loops are three-stranded, RNA–DNA hybrid, nucleic acid structures produced due to inappropriate processing of newly transcribed RNA or transcription-replication collision (TRC). Although R-loops are important for many cellular processes, their accumulation causes genomic instability and malignant diseases, so these structures are tightly regulated. It was recently reported that R-loop accumulation is resolved by methyltransferase-like 3 (METTL3)-mediated m6A RNA methylation under physiological conditions. However, it remains unclear how R-loops in the genome are recognized and induce resolution signals. Here, we demonstrate that tonicity-responsive enhancer binding protein (TonEBP) recognizes R-loops generated by DNA damaging agents such as ultraviolet (UV) or camptothecin (CPT). Single-molecule imaging and biochemical assays reveal that TonEBP preferentially binds a R-loop via both 3D collision and 1D diffusion along DNA in vitro. In addition, we find that TonEBP recruits METTL3 to R-loops through the Rel homology domain (RHD) for m6A RNA methylation. We also show that TonEBP recruits RNaseH1 to R-loops through a METTL3 interaction. Consistent with this, TonEBP or METTL3 depletion increases R-loops and reduces cell survival in the presence of UV or CPT. Collectively, our results reveal an R-loop resolution pathway by TonEBP and m6A RNA methylation by METTL3 and provide new insights into R-loop resolution processes.
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