AKT- dependent nuclear localization of EPRS1 activates PARP1 in breast cancer cells

• 成果类型: Article
• 署名作者: Zin, Isaac; China, Arnab; Khan, Krishnendu; Nag, Jeetendra K.; Vasu, Kommireddy; Deshpande, Gauravi M.; Ghosh, Prabar K.; Khan, Debjit; Ramachandiran, Iyappan; Ganguly, Shinjini; Tamagno, Ilaria; Willard, Belinda; Gogonea, Valentin; Fox, Paul L.
• 署名单位: Cleveland Clinic Foundation; University System of Ohio; Cleveland State University; Cleveland Clinic Foundation; Gandhi Institute of Technology & Management (GITAM); Cleveland Clinic Foundation; Cleveland Clinic Foundation
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14659
• DOI: 10.1073/pnas.2303642121
• 发表日期: 2024-07-23
• 关键词: transfer-rna synthetase; noncanonical function; dna-repair; bmn 673; PATHWAY; phosphorylation; transcription; inhibitors; domains; potent

摘要

Glutamyl- prolyl-tRNA synthetase (EPRS1) is a bifunctional aminoacyl-tRNA- synthetase (aaRS) essential for decoding the genetic code. EPRS1 resides, with seven other aaRSs and three noncatalytic proteins, in the cytoplasmic multi-tRNA synthetase complex (MSC). Multiple MSC- resident aaRSs, including EPRS1, exhibit stimulus- dependent release from the MSC to perform noncanonical activities distinct from their primary function in protein synthesis. Here, we show EPRS1 is present in both cytoplasm and nucleus of breast cancer cells with constitutively low phosphatase and tensin homolog (PTEN) expression. EPRS1 is primarily cytosolic in PTEN- expressing cells, but chemical or genetic inhibition of PTEN, or chemical or stress- mediated activation of its target, AKT, induces EPRS1 nuclear localization. Likewise, preferential nuclear localization of EPRS1 was observed in invasive ductal carcinoma that were also P- Ser473-AKT+. EPRS1 nuclear transport requires a nuclear localization signal (NLS) within the linker region that joins the catalytic glutamyl-tRNA synthetase and prolyl-tRNA synthetase domains. Nuclear EPRS1 interacts with poly(ADP- ribose) polymerase 1 (PARP1), a DNA- damage sensor that directs poly(ADP- ribosyl)ation (PARylation) of proteins. EPRS1 is a critical regulator of PARP1 activity as shown by markedly reduced ADP- ribosylation in EPRS1 knockdown cells. Moreover, EPRS1 and PARP1 knockdown comparably alter the expression of multiple tumor- related genes, inhibit DNA- damage repair, reduce tumor cell survival, and diminish tumor sphere formation by breast cancer cells. EPRS1- mediated regulation of PARP1 activity provides a mechanistic link between PTEN loss in breast cancer cells, PARP1 activation, and cell survival and tumor growth. Targeting the noncanonical activity of EPRS1, without inhibiting canonical tRNA ligase activity, provides a therapeutic approach potentially supplementing existing PARP1 inhibitors.