文章：

小分子抑制CBX4/7通过损害CtIP介导的DNA末端切除使同源重组缺陷型癌症对放射治疗高度敏感

Small-Molecule Inhibition of CBX4/7 Hypersensitises Homologous Recombination-Impaired Cancer to Radiation by Compromising CtIP-Mediated DNA End Resection

原文发布日期：6 June 2024

DOI: 10.3390/cancers16112155

类型: Article

开放获取: 是

英文摘要：

The therapeutic targeting of DNA repair pathways is an emerging concept in cancer treatment. Compounds that target specific DNA repair processes, such as those mending DNA double-strand breaks (DSBs), are therefore of therapeutic interest. UNC3866 is a small molecule that targets CBX4, a chromobox protein, and a SUMO E3 ligase. As a key modulator of DNA end resection—a prerequisite for DSB repair by homologous recombination (HR)—CBX4 promotes the functions of the DNA resection factor CtIP. Here, we show that treatment with UNC3866 markedly sensitises HR-deficient, NHEJ-hyperactive cancer cells to ionising radiation (IR), while it is non-toxic in selected HR-proficient cells. Consistent with UNC3866 targeting CtIP functions, it inhibits end-resection-dependent DNA repair including HR, alternative end joining (alt-EJ), and single-strand annealing (SSA). These findings raise the possibility that the UNC3866-mediated inhibition of end resection processes we define highlights a distinct vulnerability for the selective killing of HR-ineffective cancers.

摘要翻译： 

靶向DNA修复通路是癌症治疗领域的一个新兴概念。因此，针对特定DNA修复过程（如修复DNA双链断裂）的化合物具有治疗价值。UNC3866是一种靶向染色盒蛋白CBX4（一种SUMO E3连接酶）的小分子化合物。作为DNA末端切除（同源重组修复双链断裂的先决条件）的关键调控因子，CBX4能促进DNA切除因子CtIP的功能。本研究表明，UNC3866处理能显著增强同源重组缺陷且非同源末端连接过度活跃的癌细胞对电离辐射的敏感性，而在选定的同源重组功能正常的细胞中则无毒性。与UNC3866靶向CtIP功能的作用一致，该化合物能抑制依赖末端切除的DNA修复途径，包括同源重组、替代性末端连接和单链退火。这些发现提示，UNC3866介导的末端切除过程抑制可能揭示了一种选择性杀伤同源重组低效癌细胞的独特脆弱性。

原文链接：

Small-Molecule Inhibition of CBX4/7 Hypersensitises Homologous Recombination-Impaired Cancer to Radiation by Compromising CtIP-Mediated DNA End Resection