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Chemical Proteomics of the Tumor Suppressor Fhit Covalently Bound to the Cofactor Ap3A Elucidates Its Inhibitory Action on Translation

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2022

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Journal of the American Chemical Society (JACS). American Chemical Society. 2022, 144(19), pp. 8613-8623. ISSN 0002-7863. eISSN 1520-5126. Available under: doi: 10.1021/jacs.2c00815

Zusammenfassung

The tumor suppressor protein fragile histidine triad (Fhit) is known to be associated with genomic instability and apoptosis. The tumor-suppressive function of Fhit depends on the interaction with the alarmone diadenosine triphosphate (Ap3A), a noncanonical nucleotide whose concentration increases upon cellular stress. How the Fhit–Ap3A complex exerts its signaling function is unknown. Here, guided by a chemical proteomics approach employing a synthetic stable Fhit–Ap3A complex, we found that the Fhit–Ap3A complex, but not Fhit or Ap3A alone, impedes translation. Our findings provide a mechanistic model in which Fhit translocates from the nucleolus into the cytosol upon stress to form an Fhit–Ap3A complex. The Fhit–Ap3A complex impedes translation both in vitro and in vivo, resulting in reduced cell viability. Overall, our findings provide a mechanistic model by which the tumor suppressor Fhit collaborates with the alarmone Ap3A to regulate cellular proliferation.

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570 Biowissenschaften, Biologie

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ISO 690HERZOG, Doreen, Jasmin JANSEN, Maite MISSUN, Kay DIEDERICHS, Florian STENGEL, Andreas MARX, 2022. Chemical Proteomics of the Tumor Suppressor Fhit Covalently Bound to the Cofactor Ap3A Elucidates Its Inhibitory Action on Translation. In: Journal of the American Chemical Society (JACS). American Chemical Society. 2022, 144(19), pp. 8613-8623. ISSN 0002-7863. eISSN 1520-5126. Available under: doi: 10.1021/jacs.2c00815
BibTex
@article{Herzog2022-05-18Chemi-57545,
  year={2022},
  doi={10.1021/jacs.2c00815},
  title={Chemical Proteomics of the Tumor Suppressor Fhit Covalently Bound to the Cofactor Ap<sub>3</sub>A Elucidates Its Inhibitory Action on Translation},
  number={19},
  volume={144},
  issn={0002-7863},
  journal={Journal of the American Chemical Society (JACS)},
  pages={8613--8623},
  author={Herzog, Doreen and Jansen, Jasmin and Mißun, Maite and Diederichs, Kay and Stengel, Florian and Marx, Andreas}
}
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