The RNA-binding protein FMRP facilitates the nuclear export of N6-methyladenosine-containing mRNAs

  • J Biol Chem. 2019 Dec 27;294(52):19889-19895. doi: 10.1074/jbc.AC119.010078.
Phillip J Hsu  1  2 ,  Hailing Shi  1 ,  Allen C Zhu  1  3 ,  Zhike Lu  1 ,  Nimrod Miller  4 ,  Brittany M Edens  4 ,  Yongchao C Ma  5 ,  Chuan He  6  7
Affiliations
  • 1. Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637.
  • 2. Medical Scientist Training Program/Committee on Immunology, University of Chicago, Chicago, Illinois 60637.
  • 3. Medical Scientist Training Program/Committee on Cancer Biology, University of Chicago, Chicago, Illinois 60637.
  • 4. Departments of Pediatrics, Neurology and Physiology, Northwestern University Feinberg School of Medicine, Anne and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois 60611.
  • 5. Departments of Pediatrics, Neurology and Physiology, Northwestern University Feinberg School of Medicine, Anne and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois 60611 [email protected].
  • 6. Department of Chemistry and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637 [email protected].
  • 7. Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637.
PMID: 31753916 DOI: 10.1074/jbc.AC119.010078
Abstract

N6-Methyladenosine (m6A) is the most abundant post-transcriptional mRNA modification in eukaryotes and exerts many of its effects on gene expression through reader proteins that bind specifically to m6A-containing transcripts. Fragile X mental retardation protein (FMRP), an RNA-binding protein, has previously been shown to affect the translation of target mRNAs and trafficking of mRNA granules. Loss of function of FMRP causes fragile X syndrome, the most common form of inherited intellectual disability in humans. Using HEK293T cells, siRNA-mediated gene knockdown, cytoplasmic and nuclear fractions, RNA-Seq, and LC-MS/MS analyses, we demonstrate here that FMRP binds directly to a collection of m6A sites on mRNAs. FMRP depletion increased mRNA m6A levels in the nucleus. Moreover, the abundance of FMRP targets in the cytoplasm relative to the nucleus was decreased in Fmr1-KO mice, an effect also observed in highly methylated genes. We conclude that FMRP may affect the nuclear export of m6A-modified RNA targets.

Keywords
FMRP; Fmr1 KO mice; N6-methyladenosine (m6A); RNA metabolism; RNA methylation; RNA-binding protein; fragile X mental retardation protein (FMRP); gene regulation; mouse; mouse brain; neurological disease; nuclear RNA; nuclear RNA export; post-transcriptional modification.