FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression

Cell Rep. 2020 Apr 7;31(1):107464. doi: 10.1016/j.celrep.2020.03.028.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism*
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / physiology
  • Animals
  • Cell Cycle / physiology
  • Cell Division / physiology
  • Cell Line
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism*
  • Cyclin-Dependent Kinases / metabolism
  • Demethylation
  • G1 Phase / physiology
  • Heterografts
  • Humans
  • Male
  • Mice
  • Phosphorylation
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*

Substances

  • CCND1 protein, human
  • RNA, Messenger
  • Cyclin D1
  • N6-methyladenosine (m6A)
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human
  • Cyclin-Dependent Kinases
  • Adenosine