DOCK7 protects against replication stress by promoting RPA stability on chromatin

  • Nucleic Acids Res. 2021 Apr 6;49(6):3322-3337. doi: 10.1093/nar/gkab134.
Ming Gao  1  2 ,  Guijie Guo  1  2 ,  Jinzhou Huang  1  2 ,  Xiaonan Hou  3 ,  Hyoungjun Ham  4 ,  Wootae Kim  1  2 ,  Fei Zhao  1  2 ,  Xinyi Tu  1  2 ,  Qin Zhou  1  2 ,  Chao Zhang  1  2 ,  Qian Zhu  1  2 ,  Jiaqi Liu  1  2 ,  Yuanliang Yan  1  2 ,  Zhijie Xu  1  2 ,  Ping Yin  1  2 ,  Kuntian Luo  1  2 ,  John Weroha  3 ,  Min Deng  1  2 ,  Daniel D Billadeau  4 ,  Zhenkun Lou  1  2
Affiliations
  • 1. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
  • 2. Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • 3. Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • 4. Department of Biochemistry and Molecular Biology, Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
PMID: 33704464 DOI: 10.1093/nar/gkab134
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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