PDF(Pubmed)
Abstract：
Protein phosphatase 1 catalytic subunit gamma (PPP1CC) promotes DNA repair and tumor development and progression, however, its underlying mechanisms remain unclear. This study investigated the molecular mechanism of PPP1CC\'s involvement in DNA repair and the potential clinical implications. High expression of PPP1CC was significantly correlated with radioresistance and poor prognosis in human nasopharyngeal carcinoma (NPC) patients. The mechanistic study revealed that PPP1CC bound to Ku70/Ku80 heterodimers and activated DNA-PKcs by promoting DNA-PK holoenzyme formation, which enhanced nonhomologous end junction (NHEJ) -mediated DNA repair and led to radioresistance. Importantly, BRCA1-BRCA2-containing complex subunit 3 (BRCC3) interacted with PPP1CC to enhance its stability by removing the K48-linked polyubiquitin chain at Lys234 to prevent PPP1CC degradation. Therefore, BRCC3 helped the overexpressed PPP1CC to maintain its high protein level, thereby sustaining the elevation of DNA repair capacity and radioresistance. Our study identified the molecular mechanism by which PPP1CC promotes NHEJ-mediated DNA repair and radioresistance, suggesting that the BRCC3-PPP1CC-Ku70 axis is a potential therapeutic target to improve the efficacy of radiotherapy.
摘要：
蛋白磷酸酶1催化亚基γ（PPP1CC）促进DNA修复和肿瘤的发生发展，然而,其潜在机制仍不清楚。本研究探讨了PPP1CC参与DNA修复的分子机制及其潜在的临床意义。PPP1CC的高表达与鼻咽癌（NPC）患者的放射抵抗和不良预后显着相关。机理研究表明，PPP1CC通过促进DNA-PK全酶的形成与Ku70/Ku80异二聚体结合并激活DNA-PKcs，增强了非同源末端连接（NHEJ）介导的DNA修复并导致了放射抗性。重要的是,含有BRCA1-BRCA2的复合物亚基3（BRCC3）与PPP1CC相互作用，通过去除Lys234处的K48连接的聚泛素链以防止PPP1CC降解来增强其稳定性。因此,BRCC3帮助过表达的PPP1CC维持其高蛋白质水平，从而维持DNA修复能力和放射抗性的提高。我们的研究确定了PPP1CC促进NHEJ介导的DNA修复和放射抗性的分子机制，提示BRCC3-PPP1CC-Ku70轴是提高放疗疗效的潜在治疗靶点。
