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.
Highlights
DNA damage is one of the most dangerous forms of cellular stress
We examined U2-OS Set7/9KD cells along with the parental cells expressing non-specific shRNA for their ability to induce cell cycle arrest and apoptosis in response to genotoxic stress elicited by doxorubicin by FACs (Figure 1B)
Our results suggested that down-regulation of Set7/9 in osteosarcoma U2-OS cells led to defects in DNA repair and enhanced apoptosis (Figure 2D)
Summary
Genotoxic stress may be caused by both extrinsic and intrinsic factors, such as gamma- and UV-irradiation, DNA replication stress, reactive oxygen species and others. Among those double-strand breaks are considered to be the most deleterious to cells. There are two major pathways of DNA repair dealing with this type of lesions: non-homologous end joining (NHEJ) and homologous recombination (HR) [2]. These two mechanisms are initiated by several members of the phosphoinositol-3 kinase family (PI3) members exerted by different protein complexes. The first two (ATM and DNA-PK) are activated in response to double-strand breaks (DSB), whereas ATR is activated in response to stalled replication and transcription forks [3]
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