DOCK7 protects against replication stress by promoting RPA stability on chromatin |
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| Authors: | Ming Gao Guijie Guo Jinzhou Huang Xiaonan Hou Hyoungjun Ham Wootae Kim Fei Zhao Xinyi Tu Qin Zhou Chao Zhang Qian Zhu Jiaqi Liu Yuanliang Yan Zhijie Xu Ping Yin Kuntian Luo John Weroha Min Deng Daniel D Billadeau Zhenkun Lou |
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| Institution: | Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA;Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA;Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA;Department of Biochemistry and Molecular Biology, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA |
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| 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. |
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