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Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics.

TitleLeucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics.
Publication TypeJournal Article
Year of Publication2022
AuthorsPassarelli MC, Pinzaru AM, Asgharian H, Liberti MV, Heissel S, Molina H, Goodarzi H, Tavazoie SF
JournalNat Cell Biol
Volume24
Issue3
Pagination307-315
Date Published2022 Mar
ISSN1476-4679
Abstract

Tumourigenesis and cancer progression require enhanced global protein translation1-3. Such enhanced translation is caused by oncogenic and tumour-suppressive events that drive the synthesis and activity of translational machinery4,5. Here we report the surprising observation that leucyl-tRNA synthetase (LARS) becomes repressed during mammary cell transformation and in human breast cancer. Monoallelic genetic deletion of LARS in mouse mammary glands enhanced breast cancer tumour formation and proliferation. LARS repression reduced the abundance of select leucine tRNA isoacceptors, leading to impaired leucine codon-dependent translation of growth suppressive genes, including epithelial membrane protein 3 (EMP3) and gamma-glutamyltransferase 5 (GGT5). Our findings uncover a tumour-suppressive tRNA synthetase and reveal that dynamic repression of a specific tRNA synthetase-along with its downstream cognate tRNAs-elicits a downstream codon-biased translational gene network response that enhances breast tumour formation and growth.

DOI10.1038/s41556-022-00856-5
Alternate JournalNat Cell Biol
PubMed ID35288656
Grant ListT32GM007739 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) /
F32GM133118 / / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS) /
1F30CA247026-01 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /
R01CA240984 / / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) /

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