title: Codon optimality is a major determinant of mRNA stability.
abstract: mRNA degradation represents a critical regulated step in gene expression. Although the major pathways in turnover have been identified, accounting for disparate half-lives has been elusive. We show that codon optimality is one feature that contributes greatly to mRNA stability. Genome-wide RNA decay analysis revealed that stable mRNAs are enriched in codons designated optimal, whereas unstable mRNAs contain predominately non-optimal codons. Substitution of optimal codons with synonymous, non-optimal codons results in dramatic mRNA destabilization, whereas the converse substitution significantly increases stability. Further, we demonstrate that codon optimality impacts ribosome translocation, connecting the processes of translation elongation and decay through codon optimality. Finally, we show that optimal codon content accounts for the similar stabilities observed in mRNAs encoding proteins with coordinated physiological function. This work demonstrates that codon optimization exists as a mechanism to finely tune levels of mRNAs and, ultimately, proteins.
authors.affiliation: Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Presnyak
authors.affiliation: Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Najwa
authors.initials: N
authors.lastname: Alhusaini
authors.affiliation: Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Ying-Hsin
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Martin
authors.affiliation: Statistical Science Core in the Center for Clinical Investigation, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Morris
authors.affiliation: Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kline
authors.affiliation: Department of Genetics and Developmental Biology, Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Olson
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, 94158, USA.
authors.forename: David
authors.initials: D
authors.lastname: Weinberg
authors.affiliation: Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Kristian E
authors.initials: KE
authors.lastname: Baker
authors.affiliation: Department of Genetics and Developmental Biology, Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Brenton R
authors.initials: BR
authors.lastname: Graveley
authors.affiliation: Center for RNA Molecular Biology, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: jmc71@case.edu.
authors.forename: Jeff
authors.initials: J
authors.lastname: Coller
mesh_terms: D003062:Codon; D014176:Protein Biosynthesis; D020871:RNA Stability; D012331:RNA, Fungal / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*
chemical_list: D003062:Codon; D012331:RNA, Fungal; D012333:RNA, Messenger