title: SUMOylation of Rb enhances its binding with CDK2 and phosphorylation at early G1 phase.
abstract: Retinoblastoma protein (Rb) is a prototypical tumor suppressor that is vital to the negative regulation of the cell cycle and tumor progression. Hypo-phosphorylated Rb is associated with G0/G1 arrest by suppressing E2F transcription factor activity, whereas Rb hyper-phosphorylation allows E2F release and cell cycle progression from G0/G1 to S phase. However, the factors that regulate cyclin-dependent protein kinase (CDK)-dependent hyper-phosphorylation of Rb during the cell cycle remain obscure. In this study, we show that throughout the cell cycle, Rb is specifically small ubiquitin-like modifier (SUMO)ylated at early G1 phase. SUMOylation of Rb stimulates its phosphorylation level by recruiting a SUMO-interaction motif (SIM)-containing kinase CDK2, leading to Rb hyper-phosphorylation and E2F-1 release. In contrast, a SUMO-deficient Rb mutant results in reduced SUMOylation and phosphorylation, weakened CDK2 binding, and attenuated E2F-1 sequestration. Furthermore, we reveal that Rb SUMOylation is required for cell proliferation. Therefore, our study describes a novel mechanism that regulates Rb phosphorylation during cell cycle progression.
authors.affiliation: a Department of Ophthalmology , Eye and ENT Hospital of Fudan University , Shanghai , China.|b Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University , Shanghai , China.
authors.forename: Fengxi
authors.initials: F
authors.lastname: Meng
authors.affiliation: a Department of Ophthalmology , Eye and ENT Hospital of Fudan University , Shanghai , China.|b Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University , Shanghai , China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Qian
authors.affiliation: a Department of Ophthalmology , Eye and ENT Hospital of Fudan University , Shanghai , China.|b Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University , Shanghai , China.
authors.forename: Han
authors.initials: H
authors.lastname: Yue
authors.affiliation: a Department of Ophthalmology , Eye and ENT Hospital of Fudan University , Shanghai , China.|b Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University , Shanghai , China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.affiliation: a Department of Ophthalmology , Eye and ENT Hospital of Fudan University , Shanghai , China.|b Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University , Shanghai , China.
authors.forename: Kang
authors.initials: K
authors.lastname: Xue
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D016193:G1 Phase; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000378:metabolism*; D058207:Sumoylation
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: CDK2; Rb; SUMO-interaction motif (SIM); SUMOylation; cell cycle; phosphorylation