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Codon Usage and Amino Acid Identity Are Major Determinants of MRNA Stability in Humans

64 Pages Posted: 29 Jan 2019 Sneak Peek Status: Review Complete

See all articles by Megan E. Forrest

Megan E. Forrest

Case Western Reserve University - Center for RNA Science and Therapeutics; Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

Ashrut Narula

Hospital for Sick Children Research Institute (SickKids Research Institute), Program in Developmental and Stem Cell Biology; Hospital for Sick Children Research Institute (SickKids Research Institute), Molecular Medicine Program; University of Toronto - Department of Molecular Genetics

Thomas J. Sweet

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

Daniel Arango

National Institutes of Health (NIH), National Cancer Institute, Laboratory of Receptor Biology and Gene Expression

Gavin Hanson

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

James Ellis

Hospital for Sick Children Research Institute (SickKids Research Institute), Program in Developmental and Stem Cell Biology; University of Toronto - Department of Molecular Genetics

Shalini Oberdoerffer

National Institutes of Health (NIH), National Cancer Institute, Laboratory of Receptor Biology and Gene Expression

Jeff Coller

Case Western Reserve University - Center for RNA Science and Therapeutics; Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

Olivia S. Rissland

Hospital for Sick Children Research Institute (SickKids Research Institute), Molecular Medicine Program; University of Toronto - Department of Molecular Genetics

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Abstract

mRNA degradation is a critical, yet poorly understood, aspect of gene expression. Previ-ous studies demonstrate that codon content acts as a major determinant of mRNA stabil-ity in model organisms. In humans, the importance of open reading frame (ORF)-mediated regulation remains unclear. Here, we globally analyzed mRNA stability for both endogenous and human ORFeome collection mRNAs in human cells. Consistent with previous studies, we observed that synonymous codon usage impacts human mRNA decay. Unexpectedly, amino acid identity also acts as a driver of translation-dependent decay, meaning that primary protein sequence dictates overall mRNA levels and, conse-quently, protein abundance. Both codon usage and amino acid identity affect translational elongation rate to varying degrees in distinct organisms, with the net result being sensed by mRNA degradation machinery. In humans, interplay between ORF- and UTR-mediated control of mRNA stability may be critical to offset this fundamental relationship between protein sequence and mRNA abundance..

Keywords: mRNA stability, mRNA degradation, mRNA decay, codon optimality, human gene expression, genetic code, mRNA translation, protein synthesis, mRNA turnover

Suggested Citation

Forrest, Megan E. and Narula, Ashrut and Sweet, Thomas J. and Arango, Daniel and Hanson, Gavin and Ellis, James and Oberdoerffer, Shalini and Coller, Jeff and Rissland, Olivia S., Codon Usage and Amino Acid Identity Are Major Determinants of MRNA Stability in Humans (December 22, 2018). Available at SSRN: https://ssrn.com/abstract=3305366 or http://dx.doi.org/10.2139/ssrn.3305366
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Megan E. Forrest

Case Western Reserve University - Center for RNA Science and Therapeutics

Cleveland, OH
United States

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Ashrut Narula

Hospital for Sick Children Research Institute (SickKids Research Institute), Program in Developmental and Stem Cell Biology

555 University Avenue
Toronto, Ontario M5G 1X8
Canada

Hospital for Sick Children Research Institute (SickKids Research Institute), Molecular Medicine Program ( email )

Toronto, Ontario
Canada

University of Toronto - Department of Molecular Genetics ( email )

Toronto, Ontario
Canada

Thomas J. Sweet

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Daniel Arango

National Institutes of Health (NIH), National Cancer Institute, Laboratory of Receptor Biology and Gene Expression ( email )

Bethesda, MD
United States

Gavin Hanson

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

James Ellis

Hospital for Sick Children Research Institute (SickKids Research Institute), Program in Developmental and Stem Cell Biology

555 University Avenue
Toronto, Ontario M5G 1X8
Canada

University of Toronto - Department of Molecular Genetics

Toronto, Ontario
Canada

Shalini Oberdoerffer

National Institutes of Health (NIH), National Cancer Institute, Laboratory of Receptor Biology and Gene Expression ( email )

Bethesda, MD
United States

Jeff Coller

Case Western Reserve University - Center for RNA Science and Therapeutics ( email )

Cleveland, OH
United States

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences ( email )

2511 Overlook Road
Cleveland Heights, OH
United States

Olivia S. Rissland (Contact Author)

Hospital for Sick Children Research Institute (SickKids Research Institute), Molecular Medicine Program ( email )

Toronto, Ontario
Canada

University of Toronto - Department of Molecular Genetics ( email )

Medical Science Building, Room 4386
1 King's College Circle
Toronto, Ontario M5S 1A8
Canada

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