title: Modification of DBC1 by SUMO2/3 is crucial for p53-mediated apoptosis in response to DNA damage.
abstract: DBC1 is a major inhibitor of SIRT1, which plays critical roles in the control of diverse cellular processes, including stress response and energy metabolism. Therefore, the DBC1-SIRT1 interaction should finely be regulated. Here we report that DBC1 modification by Small Ubiquitin-like Modifier 2/3 (SUMO 2/3), but not by SUMO1, is crucial for p53 transactivation under genotoxic stress. Whereas etoposide treatment reduced the interaction of DBC1 with SENP1, it promoted that with PIAS3, resulting in an increase in DBC1 sumoylation. Remarkably, the switching from SENP1 to PIAS3 for DBC1 binding was achieved by ATM/ATR-mediated phosphorylation of DBC1. Furthermore, DBC1 sumoylation caused an increase in the DBC1-SIRT1 interaction, leading to the release of p53 from SIRT1 for transcriptional activation. Consistently, SENP1 knockdown promoted etoposide-induced apoptosis, whereas knockdown of PIAS3 or SUMO2/3 and overexpression of sumoylation-deficient DBC1 mutant inhibited it. These results establish the role of DBC1 sumoylation in the promotion of p53-mediated apoptosis in response to genotoxic stress.
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jong Ho
authors.initials: JH
authors.lastname: Park
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Seong Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Seung Wook
authors.initials: SW
authors.lastname: Yang
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Hee Min
authors.initials: HM
authors.lastname: Yoo
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Park
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Min Woo
authors.initials: MW
authors.lastname: Seong
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Seung Hyeun
authors.initials: SH
authors.lastname: Ka
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Kyu Hee
authors.initials: KH
authors.lastname: Oh
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
authors.forename: Chin Ha
authors.initials: CH
authors.lastname: Chung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D045744:Cell Line, Tumor; D004249:DNA Damage; D006801:Humans; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; C447939:SIRT1 protein, human; D056564:Sirtuin 1