Research Papers:

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

Larissa Lezina, Vasilisa Aksenova, Olga Fedorova, Daria Malikova, Oleg Shuvalov, Alexey V. Antonov, Dmitri Tentler, Alexander V. Garabadgiu, Gerry Melino, Nikolai A. Barlev _

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Oncotarget. 2015; 6:25843-25855. https://doi.org/10.18632/oncotarget.4584

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Larissa Lezina1,*, Vasilisa Aksenova1,*, Olga Fedorova1, Daria Malikova1, Oleg Shuvalov1, Alexey V. Antonov2, Dmitri Tentler1, Alexander V. Garabadgiu3, Gerry Melino2,3, Nikolai A. Barlev1,3

1Gene Expression Laboratory, Institute of Cytology, Saint-Petersburg, 194064, Russia

2MRC Toxicology Unit, Leicester, LE1 9HN, UK

3Molecular 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


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.

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