KMT Set7/9 affects genotoxic stress response via the Mdm2 axis

// Larissa Lezina 1, * , Vasilisa Aksenova 1, * , Olga Fedorova 1 , Daria Malikova 1 , Oleg Shuvalov 1 , Alexey V. Antonov 2 , Dmitri Tentler 1 , Alexander V. Garabadgiu 3 , Gerry Melino 2, 3 , Nikolai A. Barlev 1, 3 1 Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, 194064, Russia 2 MRC Toxicology Unit, Leicester, LE1 9HN, UK 3 Molecular Pharmacology Laboratory, Saint-Petersburg Institute of Technology, Saint-Petersburg, 190013, Russia * These authors have contributed equally to this work Correspondence to: Nikolai A. Barlev, e-mail: nick.a.barlev@gmail.com Keywords: Set7/9, genotoxic stress, operetta, Mdm2, DNA damage Received: July 23, 2014 Accepted: July 20, 2015 Published: August 01, 2015 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.