摘要：SummarySMYD3is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinicalin vivoanimal models. However, extensive characterizationin vitrofailed to clarifySMYD3function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of aSMYD3mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors.Graphical AbstractDisplay OmittedHighlights•SMYD3 phosphorylation by ATM favors the formation of HR complexes during DSB response•SMYD3 mediates DSB repair by promoting RAD51 recruitment at DNA damage sites•SMYD3 inhibition triggers a compensatory PARP-dependent DNA damage response•Co-targeting SMYD3/PARP leads to synthetic lethality in HR-proficient cancer cellsMolecular Biology; Cell Biology; Cancer
