title: A novel chemopreventive mechanism of selenomethionine: enhancement of APE1 enzyme activity via a Gadd45a, PCNA and APE1 protein complex that regulates p53-mediated base excision repair.
abstract: Organic selenium compounds have been documented to play a role in cancer prevention. Our previous study showed that selenomethionine (SeMet) induces p53 activation without genotoxic effects including apoptosis and cell cycle arrest. In this study, we investigated the mechanism by which organic selenium compounds promote p53-mediated base excision repair (BER) activity. Our data demonstrated for the first time that the interaction between growth arrest and DNA damage-inducible protein 45A (Gadd45a), which is a p53-activated downstream gene, and two BER-mediated repair proteins, proliferating cell nuclear antigen (PCNA) and apurinic/apyrimidinic endonuclease (APE1/Ref-1), was significantly increased in a p53-dependent manner following treatment with organic selenium compounds. Furthermore, we observed that the activity of APE1 was significantly increased in a p53-dependent manner in response to the organic selenium compounds. These results suggest that BER activity is dependent on wild-type p53 activity and is mediated by the modulation of protein interactions between Gadd45a and repair proteins in response to organic selenium compounds. We propose that p53-dependent BER activity is a distinct chemopreventive mechanism mediated by organic selenium compounds, and that this may provide insight into the development of effective chemopreventive strategies against various oxidative stresses that contribute to a variety of human diseases, particularly cancer.
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Hwa Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: Hye Lim
authors.initials: HL
authors.lastname: Kim
authors.forename: Yeo Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Weon
authors.forename: Young Rok
authors.initials: YR
authors.lastname: Seo
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D018890:Chemoprevention; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D012645:Selenomethionine / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D034741:RNA, Small Interfering; D012645:Selenomethionine; D016159:Tumor Suppressor Protein p53; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C085108:APEX1 protein, human