Elongator and codon bias regulate protein levels in mammalian peripheral neurons
- Goffena, Joy [ Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA ]
- Lefcort, Frances [ Montana State University: Cell Biology & Neuroscience ]
- Zhang, Yongqing [ Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA ]
- Lehrmann, Elin [ Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA ]
- Chaverra, Marta [ Montana State University: Cell Biology & Neuroscience ]
- Felig, Jehremy [ Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA ]
- Walters, Joseph [ Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA ]
- Buksch, Richard [ Department of Biological and Physical Sciences, Montana State University Billings, Billings, MT, USA ]
- Becker, Kevin G [ Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA ]
- George, Lynn [ Montana State University: Cell Biology & Neuroscience ]
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.