DOCK7 protects against replication stress by promoting RPA stability on chromatin

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

doi:10.1093/nar/gkab134

DOCK7 protects against replication stress by promoting RPA stability on chromatin

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	3322-3337
Number of pages	16
Journal	Nucleic acids research
Volume	49
Issue number	6
DOIs	https://doi.org/10.1093/nar/gkab134
State	Published - Apr 6 2021

ASJC Scopus subject areas

Genetics

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title = "DOCK7 protects against replication stress by promoting RPA stability on chromatin",

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.",

author = "Ming Gao and Guijie Guo and Jinzhou Huang and Xiaonan Hou and Hyoungjun Ham and Wootae Kim and Fei Zhao and Xinyi Tu and Qin Zhou and Chao Zhang and Qian Zhu and Jiaqi Liu and Yuanliang Yan and Zhijie Xu and Ping Yin and Kuntian Luo and John Weroha and Min Deng and Billadeau, {Daniel D.} and Zhenkun Lou",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.",

year = "2021",

month = apr,

day = "6",

doi = "10.1093/nar/gkab134",

language = "English (US)",

volume = "49",

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journal = "Nucleic acids research",

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TY - JOUR

T1 - DOCK7 protects against replication stress by promoting RPA stability on chromatin

AU - Gao, Ming

AU - Guo, Guijie

AU - Huang, Jinzhou

AU - Hou, Xiaonan

AU - Ham, Hyoungjun

AU - Kim, Wootae

AU - Zhao, Fei

AU - Tu, Xinyi

AU - Zhou, Qin

AU - Zhang, Chao

AU - Zhu, Qian

AU - Liu, Jiaqi

AU - Yan, Yuanliang

AU - Xu, Zhijie

AU - Yin, Ping

AU - Luo, Kuntian

AU - Weroha, John

AU - Deng, Min

AU - Billadeau, Daniel D.

AU - Lou, Zhenkun

PY - 2021/4/6

Y1 - 2021/4/6

N2 - 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.

AB - 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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JO - Nucleic acids research

JF - Nucleic acids research

IS - 6

ER -

DOCK7 protects against replication stress by promoting RPA stability on chromatin

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