Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells

Author:

Hsu Dennis J.12ORCID,Gao Jenny1ORCID,Yamaguchi Norihiro1ORCID,Pinzaru Alexandra1,Wu Qiushuang1ORCID,Mandayam Nandan1ORCID,Liberti Maria1,Heissel Søren3,Alwaseem Hanan3ORCID,Tavazoie Saeed456ORCID,Tavazoie Sohail F.1

Affiliation:

1. Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA.

2. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

3. Proteomics Resource Center, The Rockefeller University, New York, NY, USA.

4. Department of Systems Biology, Columbia University Medical Center, New York, NY, USA.

5. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.

6. Department of Biological Sciences, Columbia University, New York, NY, USA.

Abstract

Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine limitation—a feature of tumor microenvironments—is sufficient to induce arginine codon–switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced an adaptive proteomic shift toward low-arginine codon–containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons—reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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