title: SUMOylation negatively regulates the stability of CHFR tumor suppressor.
abstract: CHFR ubiquitin ligase acts as a checkpoint upon DNA damage and its functional inactivation is one of key characteristics of tumor development and metastasis. Despite the crucial role in maintaining genome integrity and cell cycle progression, little is known how CHFR stability is regulated. Here, we showed that CHFR is covalently modified by SUMO-1 at lysine 663 and subsequently destabilized by ubiquitin-proteasome system. While CHFR(K663R) substitution mutation does not alter its subcellular localization, SUMOylation-defective CHFR(K663R)-stable cells exhibit substantial growth suppression due to the increased stability of CHFR(K663R). Moreover, protein level of CHFR, not CHFR(K663R), is rapidly declined under SUMOylation-promoting conditions, and SENP2 deSUMOylating enzyme reverses its SUMO-modification. Collectively, we demonstrated that CHFR stability is regulated by SUMOylation-dependent proteasomal degradation. Therefore, our study underscores the importance of CHFR SUMOylation as a new regulatory mechanism of CHFR and highlights the emerging role of SUMOylation in modulating protein stability.
authors.affiliation: School of Biological Sciences, Research Center for Functional Cellulomics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Kwon
authors.forename: Sung Jun
authors.initials: SJ
authors.lastname: Bae
authors.forename: Myungjin
authors.initials: M
authors.lastname: Kim
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seol
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D055550:Protein Stability; D059748:Proteolysis; D058207:Sumoylation; D044767:Ubiquitin-Protein Ligases
chemical_list: D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D003546:Cysteine Endopeptidases; C501833:SENP2 protein, human; D008239:Lysine