The multifaceted functions of the Fat mass and Obesity-associated protein (FTO) in normal and cancer cells

Abstract

The last decade has seen mRNA modification emerge as a new layer of gene expression regulation. The Fat mass and obesity-associated protein (FTO) was the first identified eraser of N6-methyladenosine (m6A) adducts, the most widespread modification in eukaryotic messenger RNA. This discovery, of a reversible and dynamic RNA modification, aided by recent technological advances in RNA mass spectrometry and sequencing has led to the birth of the field of epitranscriptomics. FTO crystallized much of the attention of epitranscriptomics researchers and resulted in the publication of numerous, yet contradictory, studies describing the regulatory role of FTO in gene expression and central biological processes. These incongruities may be explained by a wide spectrum of FTO substrates and RNA sequence preferences: FTO binds multiple RNA species (mRNA, snRNA and tRNA) and can demethylate internal m6A in mRNA and snRNA, N6,2′-O-dimethyladenosine (m6Am) adjacent to the mRNA cap, and N1-methyladenosine (m1A) in tRNA. Here, we review current knowledge related to FTO function in healthy and cancer cells. In particular, we emphasize the divergent role(s) attributed to FTO in different tissues and subcellular and molecular contexts.

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

“…Liu et al reported that the knockdown of "writers" METTL3/METTL14 and "reader" YTHDF2 increased viral infection/replication, while the knockdown of "eraser" ALKBH5 decreased infection in human hepatocarcinoma (Huh7) cells after 72 hpi [802]. Their results were confirmed by Zannella et al who used rhein-an inhibitor of m 6 A "erasers"-to knockdown fat mass and obesity-associated protein (FTO) [809] in Vero cells infected by SARS-CoV-2, where a dose-dependent effect was seen after 14 hpi with interference of viral life cycle to complete blockage of infection at the highest dose used [810]. Conversely, works of others have found m 6 A "writers" and "readers" to positively regulate SARS-CoV-2 infection and replication, where their knockdowns decreased viral replication (Table 1, Figure 3).…”

N6-methyladenosine (m6A) reader IGF2BP1 facilitates clear-cell renal cell carcinoma aerobic glycolysis

“…Currently, targeted therapies are the standard treatment options for renal cell carcinoma, functioning as an oncogene or anti-oncogene in malignant tumors ( Relier, Rivals & David, 2022 ; Yang et al, 2022 ). On this basis of epigenetics modification, this regulatory effects of IGF2BP1 suggested that m 6 A could be utilized to develop new strategies for targeted therapies.…”

N6-methyladenosine (m6A) reader IGF2BP1 facilitates clear-cell renal cell carcinoma aerobic glycolysis

“…Currently, targeted therapies are the standard treatment options for renal cell carcinoma, functioning as an oncogene or anti-oncogene in malignant tumors 21,22 . On this basis of epigenetics modi cation, this regulatory effects of IGF2BP1 suggested that m 6 A could be utilized to develop new strategies for targeted therapies.…”