title: Phosphorylation and ubiquitination-dependent degradation of CABIN1 releases p53 for transactivation upon genotoxic stress.
abstract: CABIN1 acts as a negative regulator of p53 by keeping p53 in an inactive state on chromatin. Genotoxic stress causes rapid dissociation of CABIN1 and activation of p53. However, its molecular mechanism is still unknown. Here, we reveal the phosphorylation- and ubiquitination-dependent degradation of CABIN1 upon DNA damage, releasing p53 for transcriptional activation. The DNA-damage-signaling kinases, ATM and CHK2, phosphorylate CABIN1 and increase the degradation of CABIN1 protein. Knockdown or overexpression of these kinases influences the stability of CABIN1 protein showing that their activity is critical for degradation of CABIN1. Additionally, CABIN1 was found to undergo ubiquitin-dependent proteasomal degradation mediated by the CRL4DDB2 ubiquitin ligase complex. Both phosphorylation and ubiquitination of CABIN1 appear to be relevant for controlling the level of CABIN1 protein upon genotoxic stress.
authors.affiliation: Department of Biomedical Sciences, Department of Biochemistry and Molecular Biology, National Creative Research Center for Epigenome Reprogramming Network, Seoul, Republic of Korea.
authors.forename: Soo-Youn
authors.initials: SY
authors.lastname: Choi
authors.forename: Hyonchol
authors.initials: H
authors.lastname: Jang
authors.forename: Jae-Seok
authors.initials: JS
authors.lastname: Roe
authors.forename: Seong-Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Cho
authors.forename: Hong-Duk
authors.initials: HD
authors.lastname: Youn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009153:Mutagens / Q000633:toxicity; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D059748:Proteolysis; D013312:Stress, Physiological / Q000235:genetics; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; D018797:Cell Cycle Proteins; C091435:DDB1 protein, human; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases