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Elongator and codon bias regulate protein levels in mammalian peripheral neurons

Author

Listed:
  • Joy Goffena

    (Montana State University Billings)

  • Frances Lefcort

    (Montana State University)

  • Yongqing Zhang

    (National Institutes of Health)

  • Elin Lehrmann

    (National Institutes of Health)

  • Marta Chaverra

    (Montana State University)

  • Jehremy Felig

    (Montana State University Billings)

  • Joseph Walters

    (Montana State University Billings)

  • Richard Buksch

    (Montana State University Billings)

  • Kevin G. Becker

    (National Institutes of Health)

  • Lynn George

    (Montana State University Billings)

Abstract

Familial dysautonomia (FD) results from mutation in IKBKAP/ELP1, a gene encoding the scaffolding protein for the Elongator complex. This highly conserved complex is required for the translation of codon-biased genes in lower organisms. Here we investigate whether Elongator serves a similar function in mammalian peripheral neurons, the population devastated in FD. Using codon-biased eGFP sensors, and multiplexing of codon usage with transcriptome and proteome analyses of over 6,000 genes, we identify two categories of genes, as well as specific gene identities that depend on Elongator for normal expression. Moreover, we show that multiple genes in the DNA damage repair pathway are codon-biased, and that with Elongator loss, their misregulation is correlated with elevated levels of DNA damage. These findings link Elongator’s function in the translation of codon-biased genes with both the developmental and neurodegenerative phenotypes of FD, and also clarify the increased risk of cancer associated with the disease.

Suggested Citation

  • Joy Goffena & Frances Lefcort & Yongqing Zhang & Elin Lehrmann & Marta Chaverra & Jehremy Felig & Joseph Walters & Richard Buksch & Kevin G. Becker & Lynn George, 2018. "Elongator and codon bias regulate protein levels in mammalian peripheral neurons," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03221-z
    DOI: 10.1038/s41467-018-03221-z
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    Cited by:

    1. Alexandra M. Cheney & Stephanann M. Costello & Nicholas V. Pinkham & Annie Waldum & Susan C. Broadaway & Maria Cotrina-Vidal & Marc Mergy & Brian Tripet & Douglas J. Kominsky & Heather M. Grifka-Walk , 2023. "Gut microbiome dysbiosis drives metabolic dysfunction in Familial dysautonomia," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Sophie Martin & Kevin C. Allan & Otis Pinkard & Thomas Sweet & Paul J. Tesar & Jeff Coller, 2022. "Oligodendrocyte differentiation alters tRNA modifications and codon optimality-mediated mRNA decay," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    3. Rebeccah K. Stewart & Patrick Nguyen & Alain Laederach & Pelin C. Volkan & Jessica K. Sawyer & Donald T. Fox, 2024. "Orb2 enables rare-codon-enriched mRNA expression during Drosophila neuron differentiation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    4. Hsueh-Fu Wu & Wenxin Yu & Kenyi Saito-Diaz & Chia-Wei Huang & Joseph Carey & Frances Lefcort & Gerald W. Hart & Hong-Xiang Liu & Nadja Zeltner, 2022. "Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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