title: The ubiquitin-associated (UBA) domain of SCCRO/DCUN1D1 protein serves as a feedback regulator of biochemical and oncogenic activity.
abstract: Amplification of squamous cell carcinoma-related oncogene (SCCRO) activates its function as an oncogene in a wide range of human cancers. The oncogenic activity of SCCRO requires its potentiating neddylation domain, which regulates its E3 activity for neddylation. The contribution of the N-terminal ubiquitin-associated (UBA) domain to SCCRO function remains to be defined. We found that the UBA domain of SCCRO preferentially binds to polyubiquitin chains in a linkage-independent manner. Binding of polyubiquitin chains to the UBA domain inhibits the neddylation activity of SCCRO in vivo by inhibiting SCCRO-promoted nuclear translocation of neddylation components and results in a corresponding decrease in cullin-RING-ligase-promoted ubiquitination. The results of colony formation and xenograft assays showed a mutation in the UBA domain of SCCRO that reduces binding to polyubiquitin chains, significantly enhancing its oncogenic activity. Analysis of 47 lung and head and neck squamous cell carcinomas identified a case with a frameshift mutation in SCCRO that putatively codes for a protein that lacks a UBA domain. Analysis of data from The Cancer Genome Atlas showed that recurrent mutations cluster in the UBA domains of SCCRO, lose the ability to bind to polyubiquitinated proteins, and have increased neddylation and transformation activities. Combined, these data suggest that the UBA domain functions as a negative regulator of SCCRO function. Mutations in the UBA domain lead to loss of inhibitory control, which results in increased biochemical and oncogenic activity. The clustering of mutations in the UBA domain of SCCRO suggests that mutations may be a mechanism of oncogene activation in human cancers.
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Guochang
authors.initials: G
authors.lastname: Huang
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Towe
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Lydia
authors.initials: L
authors.lastname: Choi
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yonekawa
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Claire C
authors.initials: CC
authors.lastname: Bommeljé
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Sarina
authors.initials: S
authors.lastname: Bains
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Willi
authors.initials: W
authors.lastname: Rechler
authors.affiliation: Molecular, Microbial, and Structural Biology, University of Connecticut Health Center, Farmington, Connecticut 06030.
authors.forename: Bing
authors.initials: B
authors.lastname: Hao
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and.
authors.forename: Yegnanarayana
authors.initials: Y
authors.lastname: Ramanathan
authors.affiliation: From the Department of Surgery, Laboratory of Epithelial Cancer Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065 and singhb@mskcc.org.
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Singh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D000075687:NEDD8 Protein; D041681:NIH 3T3 Cells; D017434:Protein Structure, Tertiary; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D014162:Transfection; D025801:Ubiquitin / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
chemical_list: C408631:DCUN1D1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D014452:Ubiquitins
keywords: DCUN1D1; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma (HNSCC); Neddylation; Oncogene; SCCRO; Ubiquitin; Ubiquitin Binding Domain; Ubiquitin-associated Domain; Ubiquitination