FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression

N6-Methyladenosine (m6A) modification is the major chemical modification in mRNA that controls fundamental biological processes, including cell proliferation. Herein, we demonstrate that fat mass and obesity-associated (FTO) demethylates m6A modification of cyclin D1, the key regulator for G1 phase progression and controls cell proliferation in vitro and in vivo. FTO depletion upregulates cyclin D1 m6A modification, which in turn accelerates the degradation of cyclin D1 mRNA, leading to the impairment of G1 progression. m6A modification of cyclin D1 oscillates in a cell-cycle-dependent manner; m6A levels are suppressed during the G1 phase and enhanced during other phases. Low m6A levels during G1 are associated with the nuclear translocation of FTO from the cytosol. Furthermore, nucleocytoplasmic shuttling of FTO is regulated by casein kinase II-mediated phosphorylation of FTO. Our results highlight the role of m6A in regulating cyclin D1 mRNA stability and add another layer of complexity to cell-cycle regulation. [Display omitted] •FTO deficiency suppresses cyclin D1 mRNA levels and induces a prolonged G1 phase•FTO demethylates m6A-modified cyclin D1 mRNA and sustains its expression•m6A modification of cyclin D1 mRNA oscillates in a cell-cycle-dependent manner•Nucleocytoplasmic shuttling of FTO regulates cyclin D1 m6A modification Hirayama et al. show that FTO, the demethylase for m6A modification, regulates G1 cell-cycle progression by targeting cyclin D1 mRNA. Their studies indicate that m6A modification of mRNA can be periodically regulated during the cell cycle and that m6A demethylase FTO may be a therapeutic target for cancer treatment.