Abstract
ABSTRACTThe origin and evolution of cancer cells is considered to be mainly fueled by DNA mutations. Although translation errors could also expand the cellular proteome, their role in cancer biology remains poorly understood. Tumor suppressors called caretakers block cancer initiation and progression by preventing DNA mutations and/or stimulating DNA repair. If translational errors contribute to tumorigenesis, then caretaker genes should prevent such errors in normal cells in response to oncogenic stimuli. Here, we show that the process of cellular senescence induced by oncogenes, tumor suppressors or chemotherapeutic drugs is associated with a reduction in translational readthrough (TR) measured using reporters containing termination codons withing the context of both normal translation termination or programmed TR. Senescence reduced both basal TR and TR stimulated by aminoglycosides. Mechanistically, the reduction of TR during senescence is controlled by the RB tumor suppressor pathway. Cells that escape from cellular senescence either induced by oncogenes or chemotherapy have an increased TR. Also, breast cancer cells that escape from therapy-induced senescence express high levels of AGO1x, a TR isoform of AGO1 linked to breast cancer progression. We propose that senescence and the RB pathway reduce TR limiting proteome diversity and the expression of TR proteins required for cancer cell proliferation.
Highlights
Cellular senescence is a tumor suppressor mechanism that prevents proliferation in cells bearing oncogenic stimuli (Collado and Serrano, 2010)
Translation termination is improved in oncogene-induced senescence To investigate the effect of cellular senescence on translational readthrough (TR) efficiency, we first used a model of oncogene-induced senescence (OIS) in human primary cells
They were transduced with luciferase reporter plasmids containing either: 1) a TGA within an artificial intercistronic region (UGA readthrough); 2) the stop codon context from AQP4, a well-known mammalian readthrough candidate (Loughran et al, 2014); or 3) the non-readthrough controls (TGA mutated to CGA) between Renilla luciferase (Rluc) and Firefly luciferase (Fluc) fusion protein gene (Figure 1A)
Summary
Cellular senescence is a tumor suppressor mechanism that prevents proliferation in cells bearing oncogenic stimuli (Collado and Serrano, 2010). Senescent cells can efficiently halt tumor progression by remaining out of the cell cycle permanently as benign lesions (Collado and Serrano, 2010; Vernier and Ferbeyre, 2014). They activate their elimination through immune mediated clearance (Kang et al, 2011; Xue et al, 2007). Most senescent cells activate the p53 and retinoblastoma (RB) tumor suppressor pathways that block cell cycle progression (Collado and Serrano, 2010; Vernier et al, 2011; Vernier and Ferbeyre, 2014). Little is known about the contribution of translational errors in tumorigenesis
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