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 FBW7Î± isoform and its ubiquitination is regulated following modulation of the GSK3Î² kinase. Mutation of T428A/T432A within the degron impaired polyubiquitination upon FBW7Î± and GSK3Î² 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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|Titolo:||NONO ubiquitination is mediated by FBW7 and GSK3 Î² via a degron lost upon chromosomal rearrangement in cancer|
|Appare nelle tipologie:||1.1 Articolo in rivista|