1. Biochemistry and Chemical Biology
  2. Cell Biology
Download icon

YTHDC1 Mediates Nuclear Export of N6-methyladenosine Methylated mRNAs

  1. Ian A Roundtree
  2. Guan-Zheng Luo
  3. Zijie Zhang
  4. Xiao Wang
  5. Tao Zhou
  6. Yiquang Cui
  7. Jiahao Sha
  8. Xingxu Huang
  9. Laura Guerrero
  10. Phil Xie
  11. Emily He
  12. Bin Shen  Is a corresponding author
  13. Chuan He  Is a corresponding author
  1. University of Chicago, United States
  2. ShanghaiTech University, China
  3. Nanjing Medical University, China
  4. The University of Chicago, United States
Research Article
  • Cited 222
  • Views 5,969
  • Annotations
Cite this article as: eLife 2017;6:e31311 doi: 10.7554/eLife.31311

Abstract

N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNA (mRNA), and plays critical roles in RNA biology. The function of this modification is mediated by m6A-selective 'reader' proteins of the YTH family, which incorporate m6A-modified mRNAs into pathways of RNA metabolism. Here, we show that the m6A-binding protein YTHDC1 mediates export of methylated mRNA from the nucleus to the cytoplasm in HeLa cells. Knockdown of YTHDC1 results in an extended residence time for nuclear m6A-containing mRNA, with an accumulation of transcripts in the nucleus and accompanying depletion within the cytoplasm. YTHDC1 interacts with the splicing factor and nuclear export adaptor protein SRSF3, and facilitates RNA binding to both SRSF3 and NXF1. This role for YTHDC1 expands the potential utility of chemical modification of mRNA, and supports an emerging paradigm of m6A as a distinct biochemical entity for selective processing and metabolism of mammalian mRNAs.

Data availability

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Ian A Roundtree

    Department of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Guan-Zheng Luo

    Department of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Zijie Zhang

    Department of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Xiao Wang

    Department of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Tao Zhou

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yiquang Cui

    State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jiahao Sha

    State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Xingxu Huang

    School of Life Science and Technology, ShanghaiTech University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Laura Guerrero

    Department of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Phil Xie

    Department of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Emily He

    Department of Chemistry, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Bin Shen

    State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, Nanjing, China
    For correspondence
    binshen@njmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  13. Chuan He

    Department of Chemistry, The University of Chicago, Chicago, United States
    For correspondence
    chuanhe@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4319-7424

Funding

National Institute of General Medical Sciences (F30GM117646)

  • Ian A Roundtree

Howard Hughes Medical Institute

  • Ian A Roundtree
  • Guan-Zheng Luo
  • Zijie Zhang
  • Xiao Wang
  • Chuan He

National Science Foundation (CHE-1048528)

  • Ian A Roundtree
  • Guan-Zheng Luo
  • Zijie Zhang
  • Xiao Wang
  • Laura Guerrero
  • Phil Xie
  • Emily He
  • Chuan He

National Institute of General Medical Sciences (HG008688)

  • Chuan He

National Institute of General Medical Sciences (GM113194)

  • Chuan He

National Natural Science Foundation of China (31171377)

  • Xingxu Huang

National Natural Science Foundation of China (31471400)

  • Xingxu Huang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Nick J Proudfoot, University of Oxford, United Kingdom

Publication history

  1. Received: August 17, 2017
  2. Accepted: October 4, 2017
  3. Accepted Manuscript published: October 6, 2017 (version 1)
  4. Version of Record published: October 19, 2017 (version 2)

Copyright

© 2017, Roundtree et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 5,969
    Page views
  • 1,374
    Downloads
  • 222
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    Qiang Liu et al.
    Research Article Updated

    The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted syndrome in humans. Nevertheless, whether and how TRPV3 could be therapeutically targeted remains to be elucidated. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular simulations and mutagenesis, we further uncovered key residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive therapeutics for skin inflammation.

    1. Biochemistry and Chemical Biology
    Molly C Sutherland et al.
    Research Article

    Cytochromes c are ubiquitous heme proteins in mitochondria and bacteria, all possessing a CXXCH (CysXxxXxxCysHis) motif with covalently attached heme. We describe the first in vitro reconstitution of cytochrome c biogenesis using purified mitochondrial (HCCS) and bacterial (CcsBA) cytochrome c synthases. We employ apocytochrome c and peptide analogs containing CXXCH as substrates, examining recognition determinants, thioether attachment, and subsequent release and folding of cytochrome c. Peptide analogs reveal very different recognition requirements between HCCS and CcsBA. For HCCS, a minimal 16-mer peptide is required, comprised of CXXCH and adjacent alpha helix 1, yet neither thiol is critical for recognition. For bacterial CcsBA, both thiols and histidine are required, but not alpha helix 1. Heme attached peptide analogs are not released from the HCCS active site; thus, folding is important in the release mechanism. Peptide analogs behave as inhibitors of cytochrome c biogenesis, paving the way for targeted control.