title: TOPORS modulates H2AX discriminating genotoxic stresses.
abstract: H2AX plays an important role in chromatin reorganization implicated in DNA repair and apoptosis under various DNA damaging conditions. In this study, the interaction between TOPORS (topoisomerase I-binding protein) and H2AX was verified using mammalian cell extracts exposed to diverse DNA damaging stresses such as ionizing radiation, doxorubicin, camptothecin, and hydrogen peroxide. In vitro assays for ubiquitination revealed that TOPORS functions as a novel E3 ligase for H2AX ubiquitination. TOPORS was found to be dissociated from H2AX proteins when cells were exposed to oxidative stress, but not replication-inducing DNA damaging stress. The protein stability of H2AX was decreased when TOPORS was ectopically expressed in cells, and oxidative stresses such as hydrogen peroxide and ionizing radiation induced recovery of the H2AX protein level. Therefore, these biochemical data suggest that TOPORS plays a key role in the turnover of H2AX protein, discriminating the type of DNA damaging stress.
authors.affiliation: Division of Radiation Effect Research, Radiation Health Research Institute, Korea Hydro & Nuclear Power Co., Ltd., 132-703, Seoul, Korea. bovine@khnp.co.kr
authors.forename: Ki Moon
authors.initials: KM
authors.lastname: Seong
authors.forename: Seon Young
authors.initials: SY
authors.lastname: Nam
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Kwang Hee
authors.initials: KH
authors.lastname: Yang
authors.forename: Sungkwan
authors.initials: S
authors.lastname: An
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Jin
authors.forename: Cha Soon
authors.initials: CS
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D002843:Chromatin / Q000187:drug effects / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005720:Gamma Rays / Q000009:adverse effects; D057809:HEK293 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D055550:Protein Stability / Q000187:drug effects / Q000528:radiation effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D058207:Sumoylation / Q000187:drug effects / Q000528:radiation effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000528:radiation effects
chemical_list: D000970:Antineoplastic Agents; D002843:Chromatin; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D016877:Oxidants; D011993:Recombinant Fusion Proteins; D004317:Doxorubicin; D006861:Hydrogen Peroxide; C120157:TOPORS protein, human; D044767:Ubiquitin-Protein Ligases; D002166:Camptothecin