DOCK7 protects against replication stress by promoting RPA stability on chromatin. Issue 6 (11th March 2021)

• Record Type: Journal Article
• Authors: Gao, Ming; Guo, Guijie; Huang, Jinzhou; Hou, Xiaonan; Ham, Hyoungjun; Kim, Wootae; Zhao, Fei; Tu, Xinyi; Zhou, Qin; Zhang, Chao; Zhu, Qian; Liu, Jiaqi; Yan, Yuanliang; Xu, Zhijie; Yin, Ping; Luo, Kuntian; Weroha, John; Deng, Min; Billadeau, Daniel D; Lou, Zhenkun
• Is Part Of: Nucleic acids research. Volume 49:Issue 6(2021)
• Page Start: 3322
• Page End: 3337
• Publication Date: 2021-03-11
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkab134
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: RPA is a critical factor for DNA replication and replication stress response. Surprisingly, we found that chromatin RPA stability is tightly regulated. We report that the GDP/GTP exchange factor DOCK7 acts as a critical replication stress regulator to promote RPA stability on chromatin. DOCK7 is phosphorylated by ATR and then recruited by MDC1 to the chromatin and replication fork during replication stress. DOCK7-mediated Rac1/Cdc42 activation leads to the activation of PAK1, which subsequently phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response. Moreover, DOCK7 is overexpressed in ovarian cancer and depleting DOCK7 sensitizes cancer cells to camptothecin. Taken together, our results highlight a novel role for DOCK7 in regulation of the replication stress response and highlight potential therapeutic targets to overcome chemoresistance in cancer.