Journal Article

Nucleophosmin mutations alter its nucleolar localization by impairing G-quadruplex binding at ribosomal DNA

Sara Chiarella, Antonella De Cola, Giovanni Luca Scaglione, Erminia Carletti, Vincenzo Graziano, Daniela Barcaroli, Carlo Lo Sterzo, Adele Di Matteo, Carmine Di Ilio, Brunangelo Falini, Alessandro Arcovito, Vincenzo De Laurenzi and Luca Federici

in Nucleic Acids Research

Volume 41, issue 5, pages 3228-3239
Published in print March 2013 | ISSN: 0305-1048
Published online January 2013 | e-ISSN: 1362-4962 | DOI: http://dx.doi.org/10.1093/nar/gkt001

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Nucleophosmin (NPM1) is an abundant nucleolar protein implicated in ribosome maturation and export, centrosome duplication and response to stress stimuli. NPM1 is the most frequently mutated gene in acute myeloid leukemia. Mutations at the C-terminal domain led to variant proteins that aberrantly and stably translocate to the cytoplasm. We have previously shown that NPM1 C-terminal domain binds with high affinity G-quadruplex DNA. Here, we investigate the structural determinants of NPM1 nucleolar localization. We show that NPM1 interacts with several G-quadruplex regions found in ribosomal DNA, both in vitro and in vivo. Furthermore, the most common leukemic NPM1 variant completely loses this activity. This is the consequence of G-quadruplex–binding domain destabilization, as mutations aimed at refolding the leukemic variant also result in rescuing the G-quadruplex–binding activity and nucleolar localization. Finally, we show that treatment of cells with a G-quadruplex selective ligand results in wild-type NPM1 dislocation from nucleoli into nucleoplasm. In conclusion, this work establishes a direct correlation between NPM1 G-quadruplex binding at rDNA and its nucleolar localization, which is impaired in the acute myeloid leukemia-associated protein variants.

Journal Article.  7350 words.  Illustrated.

Subjects: Chemistry ; Biochemistry ; Bioinformatics and Computational Biology ; Genetics and Genomics ; Molecular and Cell Biology

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