Citations 1
DOCK7 protects against replication stress by promoting RPA stability on chromatin
Gao, Ming , Guo, Guijie , Huang, Jinzhou , Hou, Xiaonan , Ham, Hyoungjun , Kim, Wootae , Tu, Xinyi , Zhou, Qin , Zhang, Chao , Zhu, Qian , Liu, Jiaqi , Xu, Zhijie , Luo, Kuntian, Weroha, S. John , Billadeau, Daniel D. , Yan, Yuanliang, Weroha, John, Kim, Wootae , Xu, Zhijie , Zhao, Fei , Yan, Yuanliang , Yin, Ping , Deng, Min , Lou, Zhenkun , Guo, Guijie
Nucleic Acids Research | March 2, 2021 | Volume: 49 | Issue: 6 | Pages: 3322-3337
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.