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

Paola Sanese, Candida Fasano, Giacomo Buscemi, Cinzia Bottino, Silvia Corbetta, Edoardo Fabini, Valentina Silvestri, Virginia Valentini, Vittoria Disciglio, Giovanna Forte, Martina Lepore Signorile, Katia De Marco, Stefania Bertora, Valentina Grossi, Ummu Guven, Natale Porta, Valeria Di Maio, Elisabetta Manoni, Gianluigi Giannelli, Manuela BartoliniAlberto Del Rio, Giuseppina Caretti, Laura Ottini, Cristiano Simone

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number101604
JournaliScience
Volume23
Issue number10
DOIs
Publication statusPublished - Oct 23 2020

Keywords

  • Cancer
  • Cell Biology
  • Molecular Biology

ASJC Scopus subject areas

  • General

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