DOCK7 protects against replication stress by promoting RPA stability on chromatin

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 pho...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Genome Integrity, Repair and Replication
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034614/
https://www.ncbi.nlm.nih.gov/pubmed/33704464
http://dx.doi.org/10.1093/nar/gkab134
Descripción
Sumario: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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