2. Academic Validation
  3. DOCK7 protects against replication stress by promoting RPA stability on chromatin

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

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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