Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality

SMYD3  is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical  in vivo  animal models. However, extensive characterization  in vitro  failed to clarify  SMYD3  function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a  SMYD3  mutant 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.