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Kim, Hongtae
Cancer/DNA damage Lab.
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TonEBP recognizes R-loops and initiates m6A RNA methylation for R-loop resolution

Kang, Hyun JeCheon, Na YoungPark, HyunJeong, Gyu WonYe, Byeong JinYoo, Eun JinLee, Jun HoHur, Jin-HoeLee, Eun-AKim, HongtaeLee, Kyoo-youngChoi, Soo YounLee-Kwon, WhaseonMyung, KyungjaeLee, Ja YilKwon, Hyug Moo
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NUCLEIC ACIDS RESEARCH, v.49, no.1, pp.269 - 284
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.
Oxford University Press


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