NONO ubiquitination is mediated by FBW7 and GSK3 β via a degron lost upon chromosomal rearrangement in cancer

Luigi Alfano, Antonella Caporaso, Angela Altieri, Caterina Costa, Iris M Forte, Carmelina A Iannuzzi, Daniela Barone, Antonio Giordano, Francesca Pentimalli

Research output: Contribution to journalArticle

Abstract

NONO is an RNA-binding protein involved in transcription, mRNA splicing, DNA repair, and checkpoint activation in response to UV radiation. NONO expression has been found altered in several tumor types, including prostate, colon, breast, melanoma, and in papillary renal carcinoma, in which an X chromosome inversion generates a NONO-TFE3 fusion protein. Upon such rearrangement, NONO loses its C-terminal domain. Through bioinformatics analysis, we identified a putative degron motif, known to be recognized by the Skp1-Cul1-F-box-protein (SCF) complex. Here, we evaluated how this domain could affect NONO protein biology. We showed that NONO interacts with the nuclear FBW7α isoform and its ubiquitination is regulated following modulation of the GSK3β kinase. Mutation of T428A/T432A within the degron impaired polyubiquitination upon FBW7α and GSK3β overexpression. Overall, our data suggest that NONO is likely subjected to proteasome-mediated degradation and add NONO to the list of proteins targeted by FBW7, which is itself often deregulated in cancer.

Original languageEnglish
JournalJournal of Cellular Physiology
DOIs
Publication statusPublished - 2018

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Ubiquitination
F-Box Proteins
Neoplasms
Proteins
RNA-Binding Proteins
Papillary Carcinoma
X Chromosome
Proteasome Endopeptidase Complex
Computational Biology
DNA Repair
Prostate
Melanoma
Protein Isoforms
Colon
Breast
Phosphotransferases
Radiation
Kidney
Messenger RNA
Mutation

Keywords

  • Journal Article

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NONO ubiquitination is mediated by FBW7 and GSK3 β via a degron lost upon chromosomal rearrangement in cancer. / Alfano, Luigi; Caporaso, Antonella; Altieri, Angela; Costa, Caterina; Forte, Iris M; Iannuzzi, Carmelina A; Barone, Daniela; Giordano, Antonio; Pentimalli, Francesca.

In: Journal of Cellular Physiology, 2018.

Research output: Contribution to journalArticle

Alfano, L, Caporaso, A, Altieri, A, Costa, C, Forte, IM, Iannuzzi, CA, Barone, D, Giordano, A & Pentimalli, F 2018, 'NONO ubiquitination is mediated by FBW7 and GSK3 β via a degron lost upon chromosomal rearrangement in cancer', Journal of Cellular Physiology. https://doi.org/10.1002/jcp.26269
Alfano, Luigi ; Caporaso, Antonella ; Altieri, Angela ; Costa, Caterina ; Forte, Iris M ; Iannuzzi, Carmelina A ; Barone, Daniela ; Giordano, Antonio ; Pentimalli, Francesca. / NONO ubiquitination is mediated by FBW7 and GSK3 β via a degron lost upon chromosomal rearrangement in cancer. In: Journal of Cellular Physiology. 2018.
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abstract = "NONO is an RNA-binding protein involved in transcription, mRNA splicing, DNA repair, and checkpoint activation in response to UV radiation. NONO expression has been found altered in several tumor types, including prostate, colon, breast, melanoma, and in papillary renal carcinoma, in which an X chromosome inversion generates a NONO-TFE3 fusion protein. Upon such rearrangement, NONO loses its C-terminal domain. Through bioinformatics analysis, we identified a putative degron motif, known to be recognized by the Skp1-Cul1-F-box-protein (SCF) complex. Here, we evaluated how this domain could affect NONO protein biology. We showed that NONO interacts with the nuclear FBW7α isoform and its ubiquitination is regulated following modulation of the GSK3β kinase. Mutation of T428A/T432A within the degron impaired polyubiquitination upon FBW7α and GSK3β overexpression. Overall, our data suggest that NONO is likely subjected to proteasome-mediated degradation and add NONO to the list of proteins targeted by FBW7, which is itself often deregulated in cancer.",
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AU - Alfano, Luigi

AU - Caporaso, Antonella

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AU - Costa, Caterina

AU - Forte, Iris M

AU - Iannuzzi, Carmelina A

AU - Barone, Daniela

AU - Giordano, Antonio

AU - Pentimalli, Francesca

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N2 - NONO is an RNA-binding protein involved in transcription, mRNA splicing, DNA repair, and checkpoint activation in response to UV radiation. NONO expression has been found altered in several tumor types, including prostate, colon, breast, melanoma, and in papillary renal carcinoma, in which an X chromosome inversion generates a NONO-TFE3 fusion protein. Upon such rearrangement, NONO loses its C-terminal domain. Through bioinformatics analysis, we identified a putative degron motif, known to be recognized by the Skp1-Cul1-F-box-protein (SCF) complex. Here, we evaluated how this domain could affect NONO protein biology. We showed that NONO interacts with the nuclear FBW7α isoform and its ubiquitination is regulated following modulation of the GSK3β kinase. Mutation of T428A/T432A within the degron impaired polyubiquitination upon FBW7α and GSK3β overexpression. Overall, our data suggest that NONO is likely subjected to proteasome-mediated degradation and add NONO to the list of proteins targeted by FBW7, which is itself often deregulated in cancer.

AB - NONO is an RNA-binding protein involved in transcription, mRNA splicing, DNA repair, and checkpoint activation in response to UV radiation. NONO expression has been found altered in several tumor types, including prostate, colon, breast, melanoma, and in papillary renal carcinoma, in which an X chromosome inversion generates a NONO-TFE3 fusion protein. Upon such rearrangement, NONO loses its C-terminal domain. Through bioinformatics analysis, we identified a putative degron motif, known to be recognized by the Skp1-Cul1-F-box-protein (SCF) complex. Here, we evaluated how this domain could affect NONO protein biology. We showed that NONO interacts with the nuclear FBW7α isoform and its ubiquitination is regulated following modulation of the GSK3β kinase. Mutation of T428A/T432A within the degron impaired polyubiquitination upon FBW7α and GSK3β overexpression. Overall, our data suggest that NONO is likely subjected to proteasome-mediated degradation and add NONO to the list of proteins targeted by FBW7, which is itself often deregulated in cancer.

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