Two Isoleucyl TRNAs That Decode Synonymous Codons Divergently Regulate Breast Cancer Metastatic Growth by Controlling Translation of Proliferation-regulating Genes

Overview

Journal Nat Cancer

Specialty Oncology

Date 2022 Dec 12

PMID 36510010

Authors

Lisa B Earnest-Noble

Dennis Hsu

Siyu Chen

Hosseinali Asgharian

Mandayam Nandan

Maria C Passarelli

Hani Goodarzi

Sohail F Tavazoie

Affiliations

Soon will be listed here.

Abstract

The human genome contains 61 codons encoding 20 amino acids. Synonymous codons representing a given amino acid are decoded by a set of transfer RNAs (tRNAs) called isoacceptors. We report the surprising observation that two isoacceptor tRNAs that decode synonymous codons become modulated in opposing directions during breast cancer progression. Specifically, tRNA became upregulated, whereas tRNA became repressed as breast cancer cells attained enhanced metastatic capacity. Functionally, tRNA promoted and tRNA suppressed metastatic colonization in mouse xenograft models. These tRNAs mediated opposing effects on codon-dependent translation of growth-promoting genes, consistent with genomic enrichment or depletion of their cognate codons in mitotic genes. Our findings uncover a specific isoacceptor tRNA pair that act in opposition, divergently impacting growth-regulating genes and a disease phenotype. Degeneracy of the genetic code can thus be biologically exploited by human cancer cells via tRNA isoacceptor shifts that causally facilitate the transition toward a growth-promoting state.

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