Elongator and codon bias regulate protein levels in mammalian peripheral neurons

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...

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Bibliographic Details
Published in:	Nature communications Vol. 9; no. 1; pp. 889 - 10
Main Authors:	Goffena, Joy, Lefcort, Frances, Zhang, Yongqing, Lehrmann, Elin, Chaverra, Marta, Felig, Jehremy, Walters, Joseph, Buksch, Richard, Becker, Kevin G., George, Lynn
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-03-2018 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/51 38 38/39 38/61 38/77 45 631/114/2403 631/208/199 631/337/475 631/378/87 82/58 82/80 Animals Cancer Carrier Proteins - genetics Carrier Proteins - metabolism Cells, Cultured Codon - genetics Codon - metabolism Codon bias Deoxyribonucleic acid DNA DNA damage DNA repair Dysautonomia Dysautonomia, Familial - genetics Dysautonomia, Familial - metabolism Elongation Gene expression Genes Health risks Humanities and Social Sciences Humans Intracellular Signaling Peptides and Proteins Mammals Mice Mice, Knockout multidisciplinary Multiplexing Neurons Neurons - cytology Neurons - metabolism Peptide Chain Elongation, Translational Peripheral Nerves - cytology Peripheral Nerves - metabolism Proteins - genetics Proteins - metabolism Proteomes Scaffolding Science Science (multidisciplinary) Translation
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Summary:	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. Familial dysautonomia is linked to mutations in IKBKAP, a scaffolding protein for the Elongator complex, which regulates codon-biased gene translation in yeast. Here the authors show in mammalian neurons that IKBKAP loss alters expression of codon-biased genes, including some involved in DNA damage.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-018-03221-z