m6A promotes R-loop formation to facilitate transcription termination

Yang, Xin; Liu, Qian-Lan; Xu, Wei; Zhang, Yi-Chang; Yang, Ying; Ju, Lin-Fang; Chen, Jing; Chen, Yu‐Sheng; Li, Kuan; Ren, Jie; Sun, Qianwen

doi:10.1038/s41422-019-0235-7

Cited by 128 publications

(87 citation statements)

References 14 publications

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“…Here, we show that the METTL8 complex influences R-loops formation in the nucleus (Figure 3) and it affects R-loop regulated transcription through m3C ( Figure 5). It is known that R-loops influence transcription events such as pausing and splicing, together with recent work showing METTL3 could promote R-loop formation and facilitate transcription termination via m6A (Yang et al, 2019), we believe it is likely that nucleic acid base modifications such as methylation could be a generic biologic mechanism in which R-loops are regulated. In addition, our unpublished data have suggested METTL8 could perturb circular RNA production, which is likely due to the regulatory upstream factors such as genomic R-loops.…”

Section: Non-canonical Genetic Structures and Their Regulatorsmentioning

confidence: 85%

“…Xenograft mice models also suggested that both the SAM and the SUMO domains are responsible for METTL8 tumorigenicity. The METTL family is emerging to be an interesting class of proteins that regulate various aspects of RNA metabolism such as circRNA (Zhou et al, 2017) and R-loop (Yang et al, 2019), which are both related to tumorigenesis and genome stability. .…”

Section: The Sam and Sumo Domains Are Tumorigenic In Mice Modelmentioning

confidence: 99%

“…Additionally, computational prediction of the G-rich R-Loop Zooms in R-loop DB (Jenjaroenpun et al, 2017) revealed the genome-wide distribution of R-loops, which indicates the possible link between transcription and R-loops, suggesting that the latter may constitute a fundamental structure that impacts transcriptional elongation, termination, and overall outputs. To the best of our knowledge, although R-loops are emerging as ''a double-edged sword'' to genomic structure (Skourti-Stathaki and Proudfoot, 2014), the only factor that positively regulates R-loops is METTL3 through its m6A activity (Yang et al, 2019) and the biological function of m3C remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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The SUMOylated METTL8 Induces R-loop and Tumorigenesis via m3C

Zhang

et al. 2020

iScience

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R-loops, three-stranded DNA-DNA:RNA hybrid structures, are best known for their deleterious effects on genome stability. The regulatory factors of this fundamental genetic structure remain unclear. Here, we reveal an epigenetic factor that controls R-loop stability. METTL8, a member of the methyltransferase-like protein family that methylates 3-methylcytidine (m3C), is a key factor in the R-loop regulating methyltransferase complex. Biochemical studies show that METTL8 forms a large SUMOylated nuclear RNA-binding protein complex ($0.8 mega daltons) that contains well-reported R-loop related factors. Genetic ablation of METTL8 results in an overall reduction of R-loops in cells. Interaction assays indicated METTL8 binds to RNAs and is responsible for R-loop stability on selected gene regions. Our results demonstrate that the SUMOylated METTL8 promotes tumorigenesis by affecting genetic organization primarily in, or in close proximity to, the nucleolus and impacts the formation of regulatory R-loops through its methyltransferase activity on m3C.

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Section: Non-canonical Genetic Structures and Their Regulatorsmentioning

confidence: 85%

Section: The Sam and Sumo Domains Are Tumorigenic In Mice Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The SUMOylated METTL8 Induces R-loop and Tumorigenesis via m3C

Zhang

et al. 2020

iScience

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“…R-loops are three-stranded nucleic acid structures. M6A enhances co-transcriptional R-loops, impairing readthrough activity of Pol II for efficient termination [50].…”

Section: Mettl3mentioning

confidence: 99%

Functions of N6-methyladenosine and its role in cancer

et al. 2019

Mol Cancer

976

816

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N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which is the most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests that m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A is installed by m6A methyltransferases, removed by m6A demethylases and recognized by reader proteins, which regulate of RNA metabolism including translation, splicing, export, degradation and microRNA processing. Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR. In this review, we elaborate on recent advances in research of m6A enzymes. We also highlight the underlying mechanism of m6A in cancer pathogenesis and progression. Finally, we review corresponding potential targets in cancer therapy.

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“…Furthermore, m 6 A has been shown to be present on RNA:DNA hybrids [ 136 , 137 ]. Abakir et al have shown that m 6 A can coordinate R-loop removal with the m 6 A reader, YTH-domain family member 2 (YTHDF2), contributing to genome stability [ 136 , 138 ].…”

Section: Looking Ahead: Rna Modifications and The Ddr A Role For Rnamentioning

confidence: 99%

Jack of all trades? The versatility of RNA in DNA double-strand break repair

Ketley

Gullerová

2020

Essays in Biochemistry

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Abstract The mechanisms by which RNA acts in the DNA damage response (DDR), specifically in the repair of DNA double-strand breaks (DSBs), are emerging as multifaceted and complex. Different RNA species, including but not limited to; microRNA (miRNA), long non-coding RNA (lncRNA), RNA:DNA hybrid structures, the recently identified damage-induced lncRNA (dilncRNA), damage-responsive transcripts (DARTs), and DNA damage-dependent small RNAs (DDRNAs), have been shown to play integral roles in the DSB response. The diverse properties of these RNAs, such as sequence, structure, and binding partners, enable them to fulfil a variety of functions in different cellular contexts. Additionally, RNA can be modified post-transcriptionally, a process which is regulated in response to cellular stressors such as DNA damage. Many of these mechanisms are not yet understood and the literature contradictory, reflecting the complexity and expansive nature of the roles of RNA in the DDR. However, it is clear that RNA is pivotal in ensuring the maintenance of genome integrity. In this review, we will discuss and summarise recent evidence which highlights the roles of these various RNAs in preserving genomic integrity, with a particular focus on the emerging role of RNA in the DSB repair response.

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m6A promotes R-loop formation to facilitate transcription termination

Cited by 128 publications

References 14 publications

The SUMOylated METTL8 Induces R-loop and Tumorigenesis via m3C

The SUMOylated METTL8 Induces R-loop and Tumorigenesis via m3C

Functions of N6-methyladenosine and its role in cancer

Jack of all trades? The versatility of RNA in DNA double-strand break repair

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