title: KMT Set7/9 affects genotoxic stress response via the Mdm2 axis.
abstract: Genotoxic stress inflicted by anti-cancer drugs causes DNA breaks and genome instability. DNA double strand breaks induced by irradiation or pharmacological inhibition of Topoisomerase II activate ATM (ataxia-telangiectasia-mutated) kinase signalling pathway that in turn triggers cell cycle arrest and DNA repair. ATM-dependent gamma-phosphorylation of histone H2Ax and other histone modifications, including ubiquitnylation, promote exchange of histones and recruitment of DNA damage response (DDR) and repair proteins. Signal transduction pathways, besides DDR itself, also control expression of genes whose products cause cell cycle arrest and/or apoptosis thus ultimately affecting the sensitivity of cells to genotoxic stress. In this study, using a number of experimental approaches we provide evidence that lysine-specific methyltransferase (KMT) Set7/9 affects DDR and DNA repair, at least in part, by regulating the expression of an E3 ubiquitin ligase, Mdm2. Furthermore, we show that Set7/9 physically interacts with Mdm2. Several cancer cell lines with inverse expression of Set7/9 and Mdm2 displayed diminished survival in response to genotoxic stress. These findings are signified by our bioinformatics studies suggesting that the unleashed expression of Mdm2 in cancer patients with diminished expression of Set7/9 is associated with poor survival outcome.
authors: Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, 194064, Russia.
authors: Larissa
authors: L
authors: Lezina
authors: Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, 194064, Russia.
authors: Vasilisa
authors: V
authors: Aksenova
authors: Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, 194064, Russia.
authors: Olga
authors: O
authors: Fedorova
authors: Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, 194064, Russia.
authors: Daria
authors: D
authors: Malikova
authors: Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, 194064, Russia.
authors: Oleg
authors: O
authors: Shuvalov
authors: MRC Toxicology Unit, Leicester, LE1 9HN, UK.
authors: Alexey V
authors: AV
authors: Antonov
authors: Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, 194064, Russia.
authors: Dmitri
authors: D
authors: Tentler
authors: Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg, 190013, Russia.
authors: Alexander V
authors: AV
authors: Garabadgiu
authors: MRC Toxicology Unit, Leicester, LE1 9HN, UK.|Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg, 190013, Russia.
authors: Gerry
authors: G
authors: Melino
authors: Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, 194064, Russia.|Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg, 190013, Russia.
authors: Nikolai A
authors: NA
authors: Barlev
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D019295:Computational Biology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D030541:Databases, Genetic; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D016019:Survival Analysis; D013997:Time Factors; D014162:Transfection
chemical_list: D000903:Antibiotics, Antineoplastic; C468783:H2AX protein, human; D006657:Histones; D008769:Methylnitronitrosoguanidine; D004317:Doxorubicin; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: DNA damage; Mdm2; Set7/9; genotoxic stress; operetta