iScience (Oct 2020)
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 Bartolini,
- Alberto Del Rio,
- Giuseppina Caretti,
- Laura Ottini,
- Cristiano Simone
Affiliations
- Paola Sanese
- Medical Genetics, National Institute of Gastroenterology ''S. de Bellis'' Research Hospital, Castellana Grotte, Bari 70013, Italy
- Candida Fasano
- Medical Genetics, National Institute of Gastroenterology ''S. de Bellis'' Research Hospital, Castellana Grotte, Bari 70013, Italy
- Giacomo Buscemi
- Institute of Molecular Genetics, IGM “Luigi Luca Cavalli-Sforza”, National Research Council (CNR), Pavia 27100, Italy
- Cinzia Bottino
- Department of Biosciences, University of Milan, Milan 20133, Italy
- Silvia Corbetta
- Department of Biosciences, University of Milan, Milan 20133, Italy
- Edoardo Fabini
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Bologna 40126, Italy; BioChemoInformatics Unit, Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Bologna 40129, Italy
- Valentina Silvestri
- Department of Molecular Medicine, University of Roma ''La Sapienza'', Roma 00185, Italy
- Virginia Valentini
- Department of Molecular Medicine, University of Roma ''La Sapienza'', Roma 00185, Italy
- Vittoria Disciglio
- Medical Genetics, National Institute of Gastroenterology ''S. de Bellis'' Research Hospital, Castellana Grotte, Bari 70013, Italy
- Giovanna Forte
- Medical Genetics, National Institute of Gastroenterology ''S. de Bellis'' Research Hospital, Castellana Grotte, Bari 70013, Italy
- Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology ''S. de Bellis'' Research Hospital, Castellana Grotte, Bari 70013, Italy
- Katia De Marco
- Medical Genetics, National Institute of Gastroenterology ''S. de Bellis'' Research Hospital, Castellana Grotte, Bari 70013, Italy
- Stefania Bertora
- Medical Genetics, National Institute of Gastroenterology ''S. de Bellis'' Research Hospital, Castellana Grotte, Bari 70013, Italy
- Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology ''S. de Bellis'' Research Hospital, Castellana Grotte, Bari 70013, Italy
- Ummu Guven
- Department of Biosciences, University of Milan, Milan 20133, Italy
- Natale Porta
- Department of Medical-Surgical Sciences and Biotechnology, Polo Pontino University of Roma ''La Sapienza'', Latina 04100, Italy
- Valeria Di Maio
- Department of Medical-Surgical Sciences and Biotechnology, Polo Pontino University of Roma ''La Sapienza'', Latina 04100, Italy
- Elisabetta Manoni
- BioChemoInformatics Unit, Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Bologna 40129, Italy
- Gianluigi Giannelli
- Medical Genetics, National Institute of Gastroenterology ''S. de Bellis'' Research Hospital, Castellana Grotte, Bari 70013, Italy
- Manuela Bartolini
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Bologna 40126, Italy
- Alberto Del Rio
- BioChemoInformatics Unit, Institute of Organic Synthesis and Photoreactivity (ISOF), National Research Council (CNR), Bologna 40129, Italy; Innovamol Consulting Srl, Modena 41123, Italy
- Giuseppina Caretti
- Department of Biosciences, University of Milan, Milan 20133, Italy
- Laura Ottini
- Department of Molecular Medicine, University of Roma ''La Sapienza'', Roma 00185, Italy
- Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology ''S. de Bellis'' Research Hospital, Castellana Grotte, Bari 70013, Italy; Department of Biomedical Sciences and Human Oncology (DIMO), Medical Genetics; University of Bari Aldo Moro, Bari 70124, Italy; Corresponding author
- Journal volume & issue
-
Vol. 23,
no. 10
p. 101604
Abstract
Summary: 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.
