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A short BRCA2-derived cell-penetrating peptide targets RAD51 function and confers hypersensitivity towards PARP inhibition
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2018-04-13 , DOI: 10.1158/1535-7163.mct-17-1156
Anika Trenner 1 , Julia Godau 1 , Alessandro A. Sartori 1
Affiliation  

Under conditions of genotoxic stress, cancer cells strongly rely on efficient DNA repair to survive and proliferate. The human BRCA2 tumor suppressor protein is indispensable for the repair of DNA double-strand breaks by homologous recombination (HR) by virtue of its ability to promote RAD51 loading onto single-stranded DNA. Therefore, blocking the interaction between BRCA2 and RAD51 could significantly improve the efficacy of conventional anticancer therapies. However, targeting protein–protein interaction (PPI) interfaces has proven challenging because flat and large PPI surfaces generally do not support binding of small-molecule inhibitors. In contrast, peptides are more potent for targeting PPIs but are otherwise difficult to deliver into cells. Here, we report that a synthetic 16-mer peptide derived from the BRC4 repeat motif of BRCA2 is capable of blocking RAD51 binding to BRCA2. Efficient noncytotoxic cellular uptake of a nona-arginine (R9)-conjugated version of the BRC4 peptide interferes with DNA damage–induced RAD51 foci formation and HR. Moreover, transduction of the BRC4 peptide impairs replication fork–protective function of BRCA2 and triggers MRE11-dependent degradation of nascent DNA in response to DNA replication stress. Finally, the BRC4 cell-penetrating peptide (CPP) confers selective hypersensitivity to PARP inhibition in cancer cells but spares noncancerous cells. Taken together, our data highlight an innovative approach to develop novel peptide-based DNA repair inhibitors and establish BRCA2-derived CPPs as promising anticancer agents. Mol Cancer Ther; 17(7); 1392–404. ©2018 AACR.

中文翻译:

一种短的 BRCA2 衍生的细胞穿透肽靶向 RAD51 功能并赋予对 PARP 抑制的超敏反应

在基因毒性应激条件下,癌细胞强烈依赖有效的 DNA 修复来生存和增殖。人类 BRCA2 肿瘤抑制蛋白对于通过同源重组 (HR) 修复 DNA 双链断裂是必不可少的,因为它能够促进 RAD51 加载到单链 DNA 上。因此,阻断 BRCA2 和 RAD51 之间的相互作用可以显着提高常规抗癌疗法的疗效。然而,靶向蛋白质-蛋白质相互作用 (PPI) 界面已被证明具有挑战性,因为平坦和大的 PPI 表面通常不支持小分子抑制剂的结合。相比之下,肽更有效地靶向 PPI,但难以递送到细胞中。这里,我们报告说,源自 BRCA2 的 BRC4 重复基序的合成 16 聚体肽能够阻止 RAD51 与 BRCA2 的结合。BRC4 肽的九个精氨酸 (R9) 偶联版本的有效非细胞毒性细胞摄取会干扰 DNA 损伤诱导的 RAD51 病灶形成和 HR。此外,BRC4 肽的转导会损害 BRCA2 的复制叉保护功能,并触发新生 DNA 的 MRE11 依赖性降解,以响应 DNA 复制压力。最后,BRC4 细胞穿透肽 (CPP) 赋予癌细胞对 PARP 抑制的选择性超敏反应,但不会影响非癌细胞。总之,我们的数据突出了一种创新方法来开发基于肽的新型 DNA 修复抑制剂,并将 BRCA2 衍生的 CPP 确立为有前景的抗癌剂。摩尔癌症治疗; 17(7); 1392-404。
更新日期:2018-04-13
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