title: Regulation of the CRL4(Cdt2) ubiquitin ligase and cell-cycle exit by the SCF(Fbxo11) ubiquitin ligase.
abstract: F-box proteins and DCAF proteins are the substrate binding subunits of the Skp1-Cul1-F-box protein (SCF) and Cul4-RING protein ligase (CRL4) ubiquitin ligase complexes, respectively. Using affinity purification and mass spectrometry, we determined that the F-box protein FBXO11 interacts with CDT2, a DCAF protein that controls cell-cycle progression, and recruits CDT2 to the SCF(FBXO11)complex to promote its proteasomal degradation. In contrast to most SCF substrates, which exhibit phosphodegron-dependent binding to F-box proteins, CDK-mediated phosphorylation of Thr464 present in the CDT2 degron inhibits recognition by FBXO11. Finally, our results show that the functional interaction between FBXO11 and CDT2 is evolutionary conserved from worms to humans and plays an important role in regulating the timing of cell-cycle exit.
authors.affiliation: Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 522 First Avenue, SRB 1107, New York, NY 10016, USA. mrossi@ibioba-mpsp-conicet.gov.ar
authors.forename: Mario
authors.initials: M
authors.lastname: Rossi
authors.forename: Shanshan
authors.initials: S
authors.lastname: Duan
authors.forename: Yeon-Tae
authors.initials: YT
authors.lastname: Jeong
authors.forename: Moritz
authors.initials: M
authors.lastname: Horn
authors.forename: Anita
authors.initials: A
authors.lastname: Saraf
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.forename: Michael P
authors.initials: MP
authors.lastname: Washburn
authors.forename: Adam
authors.initials: A
authors.lastname: Antebi
authors.forename: Michele
authors.initials: M
authors.lastname: Pagano
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002453:Cell Cycle; D002454:Cell Differentiation; D017124:Conserved Sequence; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: C429530:DTL protein, human; D044783:F-Box Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C457579:FBXO11 protein, human; D011484:Protein-Arginine N-Methyltransferases; D044767:Ubiquitin-Protein Ligases