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CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts

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Listed:
  • Ricardos Tabet

    (Massachusetts General Hospital and Harvard Medical School
    Broad Institute of Harvard University and MIT)

  • Laure Schaeffer

    (Université de Strasbourg, CNRS)

  • Fernande Freyermuth

    (Massachusetts General Hospital and Harvard Medical School
    Broad Institute of Harvard University and MIT)

  • Melanie Jambeau

    (Massachusetts General Hospital and Harvard Medical School
    Broad Institute of Harvard University and MIT)

  • Michael Workman

    (Massachusetts General Hospital and Harvard Medical School)

  • Chao-Zong Lee

    (Massachusetts General Hospital and Harvard Medical School)

  • Chun-Chia Lin

    (Massachusetts General Hospital and Harvard Medical School)

  • Jie Jiang

    (University of California San Diego)

  • Karen Jansen-West

    (Mayo Clinic)

  • Hussein Abou-Hamdan

    (CNRS/University of Strasbourg)

  • Laurent Désaubry

    (CNRS/University of Strasbourg)

  • Tania Gendron

    (Mayo Clinic)

  • Leonard Petrucelli

    (Mayo Clinic)

  • Franck Martin

    (Université de Strasbourg, CNRS)

  • Clotilde Lagier-Tourenne

    (Massachusetts General Hospital and Harvard Medical School
    Broad Institute of Harvard University and MIT)

Abstract

Expansion of G4C2 repeats in the C9ORF72 gene is the most prevalent inherited form of amyotrophic lateral sclerosis and frontotemporal dementia. Expanded transcripts undergo repeat-associated non-AUG (RAN) translation producing dipeptide repeat proteins from all reading frames. We determined cis-factors and trans-factors influencing translation of the human C9ORF72 transcripts. G4C2 translation operates through a 5′–3′ cap-dependent scanning mechanism, requiring a CUG codon located upstream of the repeats and an initiator Met-tRNAMeti. Production of poly-GA, poly-GP, and poly-GR proteins from the three frames is influenced by mutation of the same CUG start codon supporting a frameshifting mechanism. RAN translation is also regulated by an upstream open reading frame (uORF) present in mis-spliced C9ORF72 transcripts. Inhibitors of the pre-initiation ribosomal complex and RNA antisense oligonucleotides selectively targeting the 5′-flanking G4C2 sequence block ribosomal scanning and prevent translation. Finally, we identified an unexpected affinity of expanded transcripts for the ribosomal subunits independently from translation.

Suggested Citation

  • Ricardos Tabet & Laure Schaeffer & Fernande Freyermuth & Melanie Jambeau & Michael Workman & Chao-Zong Lee & Chun-Chia Lin & Jie Jiang & Karen Jansen-West & Hussein Abou-Hamdan & Laurent Désaubry & Ta, 2018. "CUG initiation and frameshifting enable production of dipeptide repeat proteins from ALS/FTD C9ORF72 transcripts," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02643-5
    DOI: 10.1038/s41467-017-02643-5
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    Cited by:

    1. Yoshifumi Sonobe & Jihad Aburas & Gopinath Krishnan & Andrew C. Fleming & Ghanashyam Ghadge & Priota Islam & Eleanor C. Warren & Yuanzheng Gu & Mark W. Kankel & André E. X. Brown & Evangelos Kiskinis , 2021. "A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    2. Malgorzata J. Latallo & Shaopeng Wang & Daoyuan Dong & Blake Nelson & Nathan M. Livingston & Rong Wu & Ning Zhao & Timothy J. Stasevich & Michael C. Bassik & Shuying Sun & Bin Wu, 2023. "Single-molecule imaging reveals distinct elongation and frameshifting dynamics between frames of expanded RNA repeats in C9ORF72-ALS/FTD," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Antonios Apostolopoulos & Naohiro Kawamoto & Siu Yu A. Chow & Hitomi Tsuiji & Yoshiho Ikeuchi & Yuichi Shichino & Shintaro Iwasaki, 2024. "dCas13-mediated translational repression for accurate gene silencing in mammalian cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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