Identification of TLS Inhibitors Through the Development of Imaging-Based Screening Platforms.

GARCIA I.A.; VILLAFAÑEZ M.F.; PANSA M.F.; CARBAJOSA S.; BOCCO J.L.; SORIA G.

Córdoba

Congreso; 52° Reunión Anual de la Sociedad Argentina de Investigación en Bioquímica y Biología Molecular - SAIB 2016.; 2016

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

The identification of compounds and the development of rational strategies to achieve selective cytotoxicity against cancer cells is a current challenge in cancer therapy. A strategy that has yielded promising results is the induction of synthetic lethality (SL), which takes advantage of the mutations of cancer cells to induce cell death. DNA repair pathways are strategic targets to trigger SL due to their central role in the preservation of genomic stability and cell viability. Two key DNA repair mechanisms that protect replication forks integrity are Homologous Recombination (HR) and Translesion DNA synthesis (TLS). Given that different types of tumor cells tend to lose HR, the inhibition of TLS emerges as a promising strategy for cancer therapy. However, specific chemical inhibitors of TLS are not available to date. Our main goal is to identify specific inhibitors of TLS by developing cell-based assays that explore TLS markers. TLS polymerases recruitment to sites of DNA damage is a key step of TLS, which efficiency can be indirectly examined by studying the recruitment of TLS polymerases into replication foci. Here, we show the setup of a screening platform to monitor TLS polymerases recruitment to damage sites, through an imaging-based assay.