title: SUMOylation of hnRNP-K is required for p53-mediated cell-cycle arrest in response to DNA damage.
abstract: Heterogeneous ribonucleoprotein-K (hnRNP-K) is normally ubiquitinated by HDM2 for proteasome-mediated degradation. Under DNA-damage conditions, hnRNP-K is transiently stabilized and serves as a transcriptional co-activator of p53 for cell-cycle arrest. However, how the stability and function of hnRNP-K is regulated remained unknown. Here, we demonstrated that UV-induced SUMOylation of hnRNP-K prevents its ubiquitination for stabilization. Using SUMOylation-defective mutant and purified SUMOylated hnRNP-K, SUMOylation was shown to reduce hnRNP-K's affinity to HDM2 with an increase in that to p53 for p21-mediated cell-cycle arrest. PIAS3 served as a small ubiquitin-related modifier (SUMO) E3 ligase for hnRNP-K in an ATR-dependent manner. During later periods after UV exposure, however, SENP2 removed SUMO from hnRNP-K for its destabilization and in turn for release from cell-cycle arrest. Consistent with the rise-and-fall of both SUMOylation and stability of hnRNP-K, its ability to interact with PIAS3 was inversely correlated to that with SENP2 during the time course after UV exposure. These findings indicate that SUMO modification plays a crucial role in the control of hnRNP-K's function as a p53 co-activator in response to DNA damage by UV.
authors.affiliation: Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea.
authors.forename: Seong Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Moon Hee
authors.initials: MH
authors.lastname: Lee
authors.forename: Jong Ho
authors.initials: JH
authors.lastname: Park
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Kang
authors.forename: Hee Min
authors.initials: HM
authors.lastname: Yoo
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Ka
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Oh
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Jeon
authors.forename: Chin Ha
authors.initials: CH
authors.lastname: Chung
mesh_terms: D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004249:DNA Damage; D057809:HEK293 Cells; D006367:HeLa Cells; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D058207:Sumoylation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry; D014466:Ultraviolet Rays
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D025841:Small Ubiquitin-Related Modifier Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; C501833:SENP2 protein, human