FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression

N-6-Methyladenosine (m(6)A) 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 m(6)A 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 m(6)A modification, which in turn accelerates the degradation of cyclin D1 mRNA, leading to the impairment of G1 progression. m(6)A modification of cyclin D1 oscillates in a cell-cycle-dependent manner; m(6)A levels are suppressed during the G1 phase and enhanced during other phases. Low m(6)A 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 m(6)A in regulating cyclin D1 mRNA stability and add another layer of complexity to cell-cycle regulation.