FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression

Abstract

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.

Keywords: FTO; N(6)-methyladenosine; RNA; casein kinase; cell cycle; cyclin D1; modification; phosphorylation.