Differential m6A, m6Am, and m1A Demethylation Mediated by FTO in Cell Nucleus and Cytoplasm

By Jiangbo W, Fange Liu, Zhike Lu, Qili Fei, Yuxi Ai, P. He, Hailing Shi, X. Cui, R. Su, A. Klungland and 3 more. Molecules and Cells, 2018

646 citations recorded by the source corpus.

Summary FTO, the first RNA demethylase discovered, mediates the demethylation of internal N6-methyladenosine (m6A) and N6, 2-O-dimethyladenosine (m6Am) at the +1 position from the 5’ cap in mRNA. Here, we demonstrate that the cellular distribution of FTO is distinct among different cell lines, affecting the access of FTO to different RNA substrates. We find that FTO binds multiple RNA species, including mRNA, snRNA, and tRNA, and can demethylate internal m6A and cap m6A in mRNA, internal m6m A in U6 RNA, internal and cap m6Am in snRNAs, and N1-methyladenosine (m1A) in tRNA. FTO-mediated demethylation shows a greater impact on the transcript levels of mRNAs possessing internal m6A than the ones with cap m6Am in the tested cells. We also show that FTO can directly repress translation by catalyzing m1A tRNA demethylation. Collectively, FTO-mediated RNA demethylation occurs to m6A and m6Am in mRNA and snRNA as well as m1A in tRNA.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/d9808abab34eb1769649bacab09d02724f10856c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Hailing Shi
2. Chuan He

In Molecular Biology

1. Chuan He
2. Hailing Shi
3. Jiangbo W
4. Jianjun Chen
5. R. Su
6. Samie R. Jaffrey
7. P. He
8. S. Zaccara

Citations in the corpus

• FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export (2019, neutral): “The presence of m 6 A erasers has also been revealed, suggesting the complex and dynamic regulation of m 6 A (Jia et al., 2011; Wei et al., 2018).”
• Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “The superimposition of FTO with NOP2/Sun RNA methyltransferase family member 6 (NSUN6), a known tRNA m5C methyltransferase (Haag et al., 2015), revealed similarities in their overall structures, supporting that FTO can also acts as a tRNA demethylase on stem-loop substrates (Wei et al., 2018).”
• Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia (2019, background): “Since recent reports independently showed that FTO minimally affected the expression levels of mRNA starting with m(6)Am (Akichika et al., 2019; Sun et al., 2019; Wei et al., 2018), it is likely that m6A, rather than m(6)Am, is the main substrate of FTO in AML cells (Su et al.”
• m6A RNA methylation: from mechanisms to therapeutic potential (2021, neutral): “…dioxygenases that mediate oxidative demethylation of m 6 A. ALKBH5 is a m 6 A demethylase and plays critical roles in spermatogenesis, immunity, and cancer progression, while FTO has been reported to demethylate m 6 A and m 6 A m on mRNA and m 1 A on tRNA (Wei et al , 2018).”
• Targeting FTO suppresses cancer stem cell maintenance and immune evasion (2020, neutral): “FTO KD or inhibition also increased the m6A abundance in snRNAs, hinting a role of FTO in RNA alternative splicing (Mauer et al., 2019; Wei et al., 2018).”