Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality
| Autor: | Silvia Corbetta, Vittoria Disciglio, Martina Lepore Signorile, Alberto Del Rio, Natale Porta, Valentina Grossi, Stefania Bertora, Valeria Di Maio, Manuela Bartolini, Valentina Silvestri, Giovanna Forte, Cristiano Simone, Paola Sanese, Giuseppina Caretti, Katia De Marco, Giacomo Buscemi, Laura Ottini, Cinzia Bottino, Candida Fasano, Virginia Valentini, Elisabetta Manoni, Gianluigi Giannelli, Ummu Guven, Edoardo Fabini |
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| Přispěvatelé: | Sanese, Paola, Fasano, Candida, Buscemi, Giacomo, Bottino, Cinzia, Corbetta, Silvia, Fabini, Edoardo, Silvestri, Valentina, Valentini, Virginia, Disciglio, Vittoria, Forte, Giovanna, Lepore Signorile, Martina, De Marco, Katia, Bertora, Stefania, Grossi, Valentina, Guven, Ummu, Porta, Natale, Di Maio, Valeria, Manoni, Elisabetta, Giannelli, Gianluigi, Bartolini, Manuela, Del Rio, Alberto, Caretti, Giuseppina, Ottini, Laura, Simone, Cristiano |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Mutant RAD51 02 engineering and technology Synthetic lethality medicine.disease_cause Article 03 medical and health sciences medicine carcinogenesi lcsh:Science Molecular Biology Cancer SMYD3 Multidisciplinary Chemistry cancer cell biology molecular biology Cell Biology 021001 nanoscience & nanotechnology medicine.disease Synthetic Lethality 030104 developmental biology PARP-dependent DNA damage Cancer cell Cancer research Phosphorylation lcsh:Q 0210 nano-technology Carcinogenesis Homologous recombination |
| Zdroj: | iScience, Vol 23, Iss 10, Pp 101604-(2020) iScience |
| ISSN: | 2589-0042 |
| Popis: | 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. Graphical Abstract Highlights • 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 cells Molecular Biology; Cell Biology; Cancer |
| Databáze: | OpenAIRE |
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