Specific inhibition of chromatin modifiers impairs the recruitment of DNA repair proteins at DNA damage sites

Resumen del póster presentado a la EACR Conference: Protecting the Code, Epigenetic Impacts on Genome Stability, celebrado en berlin (Alemania) del 29 de octubre al 1 de noviembre de 2017.Double-strand breaks (DSBs) are the most deleterious form of DNA damage and they can arise from external and internal sources. In order to preserve their genome integrity, eukaryotic cells have developed DNA damage signaling and repair machineries whose deployment depends on the nature of the lesion. DNA damage takes place within the complex organization of chromatin, which acts as a barrier to the efficient detection and repair of DNA lesions. Because of that, all eukaryotic DSB repair pathways involve physiological chromatin alterations that facilitate the accessibility of repair machinery at damage sites and restore its local architecture afterwards. The current challenge is to understand how DNA repair occurs in the context of a highly organized chromatin environment. During DNA damage sensing and repair, histones undergo a set of posttranslational modifications (PTMs), including acetylation and methylation. Our aim is to determine how PTMs coordinate and amplify the DNA damage response (DDR). For this purpose, different tumor cell lines were incubated with pharmacological inhibitors of chromatin modifiers, followed by induction of DNA damage by either ionizing radiation or chemotherapeutic drugs like Olaparib. Next, DNA repair foci formation was assessed, focusing on sensor and mediator proteins, such as γ-H2AX, Nbs1, MDC1 or 53BP1. Interestingly, 53BP1 foci formation was impaired after inhibiting histone acetylases and/or methylases, while the assembly of γ-H2AX ones was not affected. This supports the idea that precise PMTs are absolutely essential to 53BP1 recruitment and, thus, to DNA repair. Based on these results, we hypothesize that specific inhibitors against epigenetic marks could have potential as anti-cancer therapies, since inaccurate and inefficient repair of DSBs and changes in acetylation/methylation states would contribute to cell death in tumors.Peer Reviewe