Mitochondrial cytochrome c liberates the nucleophosmin-sequestered ARF tumor suppressor in the nucleolus

Gonzalez-Arzola, K.; Diaz-Quintana, A.; Bernardo-Garcia, N.; Casado-Combreras, M. A.; Elena-Real, C. A.; Velazquez-Cruz, A.; Gil-Caballero, S.; Velazquez-Campoy, A.; Szulc, E.; Ayala, I.; Arranz, R.; Salvatella, X.; Valpuesta, J. M.; Hermoso, J. A.; De la Rosa, M. A.; Diaz-Moreno, I.

doi:10.1101/2020.05.07.057075

bioRxiv · 10.1101/2020.05.07.057075

Mitochondrial cytochrome c liberates the nucleophosmin-sequestered ARF tumor suppressor in the nucleolus

Gonzalez-Arzola, K.·Diaz-Quintana, A.·Bernardo-Garcia, N.·Casado-Combreras, M. A.·Elena-Real, C. A.·Velazquez-Cruz, A.·Gil-Caballero, S.·Velazquez-Campoy, A.·Szulc, E.·Ayala, I.·Arranz, R.·Salvatella, X.·Valpuesta, J. M.·Hermoso, J. A.·De la Rosa, M. A.·Diaz-Moreno, I.

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Abstract

The alternative reading frame (ARF) protein is crucial in the cellular response to oncogenic stress, being likewise the second most frequently inactivated gene in a wide spectrum of human cancers. ARF is usually sequestered in the nucleolus by the well-known oncogenic nucleophosmin (NPM) protein and is liberated in response to cell damage to exhibit its tumor-suppressor ability. However, the mechanism underlying ARF activation is unknown. Here we show that mitochondria-to-nucleus translocation of cytochrome c upon DNA damage leads to the break-off of the NPM-ARF ensemble and subsequent release of ARF from the nucleoli. Our structural and subcellular data support a molecular model in which the hemeprotein triggers the extended-to-compact conformation of NPM and competes with ARF for binding to NPM.

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Gonzalez-Arzola, K., Diaz-Quintana, A., Bernardo-Garcia, N., Casado-Combreras, M. A., Elena-Real, C. A., Velazquez-Cruz, A., Gil-Caballero, S., Velazquez-Campoy, A., Szulc, E., Ayala, I., Arranz, R., Salvatella, X., Valpuesta, J. M., Hermoso, J. A., De la Rosa, M. A., Diaz-Moreno, I.. 2020-05-08. Mitochondrial cytochrome c liberates the nucleophosmin-sequestered ARF tumor suppressor in the nucleolus. https://doi.org/10.1101/2020.05.07.057075

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