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Exploring how INT6/EIF3E influences DNA repair - Implications in cancer therapy (Christelle Morris- projet 4)

We identify the antioncogenic breast cancer factor INT6/EIF3E as an essential regulator of DNA damage signaling and repair in human cells

We identify the antioncogenic breast cancer factor INT6/EIF3E as an essential regulator of DNA damage signaling and repair in human cells (Morris et al. Cancer Res., 2016). Specifically, INT6 promotes repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) and, to a lesser extent, by nonhomologous end-joining. Mechanistic insights into how INT6 facilitates HR-mediated repair have been obtained. INT6 is crucial for the accrual of the ubiquitin ligase RNF8 at DSBs and the formation of Lys63-linked polyubiquitin chains needed for the ensuing retention of repair proteins at DNA lesions. Accordingly, accumulation of the HR repair factors BRCA1, BRCA2, and RAD51 is impaired upon INT6 downregulation. This effect of INT6 on RNF8 localization at DSBs is likely due to its involvement on ATM signaling we reported previously (Morris et al., Cancer Res., 2012).

We now study whether this new activity of INT6 in HR-mediated DSB repair could be utilized to treat cancers deficient for INT6, similar to cancers with BRCA1 or BRCA2 defects. The role of BRCA1 and BRCA2 in HR-mediated repair has been exploited to develop a therapeutic option based on the synthetic lethality of BRCA-deficient cells treated with inhibitors of poly(ADP-ribose) polymerase (PARP). The repertoire of tumors that can be treated with PARP inhibitors expands now to other HR-deficient cancers.