Title | Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Passarelli MC, Pinzaru AM, Asgharian H, Liberti MV, Heissel S, Molina H, Goodarzi H, Tavazoie SF |
Journal | Nat Cell Biol |
Volume | 24 |
Issue | 3 |
Pagination | 307-315 |
Date Published | 2022 Mar |
ISSN | 1476-4679 |
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. |
DOI | 10.1038/s41556-022-00856-5 |
Alternate Journal | Nat Cell Biol |
PubMed ID | 35288656 |
Grant List | T32GM007739 / / 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) / |
Submitted by bel2021 on March 21, 2022 - 6:19pm