靶向SMYD3使同源重组 proficient肿瘤对PARP介导的合成致死敏感。 （注：这里“proficient”不太准确，结合语境可能是“ proficient in homologous recombination”，即“同源重组 proficient”可理解为“同源重组功能正常的” ，完整准确译文：靶向SMYD3使同源重组功能正常的肿瘤对PARP介导的合成致死敏感。 ）
Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality.
作者信息
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
机构信息
Medical Genetics, National Institute of Gastroenterology "S. de Bellis" Research Hospital, Castellana Grotte, Bari 70013, Italy.
Institute of Molecular Genetics, IGM "Luigi Luca Cavalli-Sforza", National Research Council (CNR), Pavia 27100, Italy.
出版信息
iScience. 2020 Oct 7;23(10):101604. doi: 10.1016/j.isci.2020.101604. eCollection 2020 Oct 23.
is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical animal models. However, extensive characterization failed to clarify function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a 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.
在多种癌症中经常过度表达。实际上，其失活会降低临床前动物模型中的肿瘤生长。然而，尽管证实了其在致癌作用中的重要性，但广泛的表征未能阐明其在癌细胞中的功能。利用在一个高危乳腺癌家族中鉴定出的突变变体，我们在此表明，ATM介导的SMYD3磷酸化能够形成一个包含ATM、SMYD3、CHK2和BRCA2的多蛋白复合物，这是RAD51最终加载到DNA双链断裂位点并完成同源重组（HR）所必需的。值得注意的是，SMYD3的药理抑制使HR功能正常的癌细胞对PARP抑制剂敏感，从而扩展了合成致死方法在人类肿瘤中的应用潜力。
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