Identification of Nanog as a novel inhibitor of Rad51.
Identification of Nanog as a novel inhibitor of Rad51.
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Nanog 鉴定为新型 Rad51 抑制剂
DOI：
10.1038/s41419-022-04644-9
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发表时间：
2022-02-26
影响因子：
9
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Xin Y;Wang J;Wu Y;Li Q;Dong M;Liu C;He Q;Wang R;Wang D;Jiang S;Xiao W;Tian Y;Zhang W
开发针对DNA损伤修复途径的抑制剂对于提高癌症患者的化疗和放射治疗效果具有重要意义。RAD51介导DNA损伤的同源重组(HR)修复。它在人类癌症中广泛过表达，通过增强HR修复信号，防止损伤引起的癌细胞死亡，从而压倒了化疗和放射造成的DNA损伤。因此，寻找RAD51的抑制剂对于实现癌症的有效治疗具有重要意义。转录因子Nanog是胚胎干细胞(ES细胞)的核心调节因子，在维持干细胞干性方面起着不可或缺的作用。在这项研究中，我们确定Nanog是一种新的RAD51抑制剂。它与RAD51相互作用，并通过其C/CD2结构域抑制RAD51介导的DNA损伤HR修复。此外，RAD51的抑制可以通过纳米材料或细胞穿透肽(CPP)介导的Nanog-C/CD2多肽直接导入体细胞癌细胞来实现。此外，我们还发现Nanog抑制了RAD51与单链DNA的结合，从而使HR修复信号停滞。本研究解释了γ在未受干扰的ES细胞和早期胚胎中的高水平，并建议纳米C/CD2RAD51相关的基础研究和治疗应用研究有希望成为候选药物。
To develop inhibitors targeting DNA damage repair pathways is important to improve the effectiveness of chemo- and radiotherapy for cancer patients. Rad51 mediates homologous recombination (HR) repair of DNA damages. It is widely overexpressed in human cancers and overwhelms chemo- and radiotherapy-generated DNA damages through enhancing HR repair signaling, preventing damage-caused cancer cell death. Therefore, to identify inhibitors of Rad51 is important to achieve effective treatment of cancers. Transcription factor Nanog is a core regulator of embryonic stem (ES) cells for its indispensable role in stemness maintenance. In this study, we identified Nanog as a novel inhibitor of Rad51. It interacts with Rad51 and inhibits Rad51-mediated HR repair of DNA damage through its C/CD2 domain. Moreover, Rad51 inhibition can be achieved by nanoscale material- or cell-penetrating peptide (CPP)-mediated direct delivery of Nanog-C/CD2 peptides into somatic cancer cells. Furthermore, we revealed that Nanog suppresses the binding of Rad51 to single-stranded DNAs to stall the HR repair signaling. This study provides explanation for the high γH2AX level in unperturbed ES cells and early embryos, and suggests Nanog-C/CD2 as a promising drug candidate applied to Rad51-related basic research and therapeutic application studies.
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影响因子：
19
作者：
Ceccaldi R;Rondinelli B;D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
11.4
作者：
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通讯作者：
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影响因子：
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Lopes M
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16
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通讯作者：
Nussenzweig MC
影响因子：
5.6
作者：
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通讯作者：
Stein, Gary S.