title: XPC promotes MDM2-mediated degradation of the p53 tumor suppressor.
abstract: Although ubiquitin receptor Rad23 has been implicated in bringing ubiquitylated p53 to the proteasome, how Rad23 recognizes p53 remains unclear. We demonstrate that XPC, a Rad23-binding protein, regulates p53 turnover. p53 protein in XPC-deficient cells remains ubiquitylated, but its association with the proteasome is drastically reduced, indicating that XPC regulates a postubiquitylation event. Furthermore, we found that XPC participates in the MDM2-mediated p53 degradation pathway via direct interaction with MDM2. XPC W690S pathogenic mutant is specifically defective for MDM2 binding and p53 degradation. p53 is known to become stabilized following UV irradiation but can be rendered unstable by XPC overexpression, underscoring a critical role of XPC in p53 regulation. Elucidation of the proteolytic role of XPC in cancer cells will help to unravel the detailed mechanisms underlying the coordination of DNA repair and proteolysis.
authors.affiliation: State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, People's Republic of China Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229 First Affiliated Hospital, Nanchang University, Jiangxi 330006, People's Republic of China.
authors.forename: Jing Yan
authors.initials: JY
authors.lastname: Krzeszinski
authors.forename: Vitnary
authors.initials: V
authors.lastname: Choe
authors.forename: Jia
authors.initials: J
authors.lastname: Shao
authors.forename: Xin
authors.initials: X
authors.lastname: Bao
authors.forename: Haili
authors.initials: H
authors.lastname: Cheng
authors.forename: Shiwen
authors.initials: S
authors.lastname: Luo
authors.forename: Keke
authors.initials: K
authors.lastname: Huo
authors.forename: Hai
authors.initials: H
authors.lastname: Rao
mesh_terms: D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C086985:RAD23A protein, human; C086984:XPC protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex; D045643:DNA Repair Enzymes