DOCK7 protects against replication stress by promoting RPA stability on chromatin

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

doi:10.1093/nar/gkab134

Cited by 13 publications

(14 citation statements)

References 58 publications

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“…DOCK7 is a RAC-GEF with the potential to regulate F-actin organization (Fig. 5 A), consistent with previous publications reporting DOCK7-mediated RAC1/CDC42 - PAK1 activation in the DNA replication stress response 122 , and the promotion of glioblastoma cell invasion by DOCK7 via RAC activation 123 . These findings identify the LPAR2 → DOCK7 axis as a novel signaling mechanism regulating actomyosin dynamics to be of similar relevance in the initiation of entosis as LPAR1.…”

Section: Discussionsupporting

confidence: 91%

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The lysophosphatidic acid-regulated signal transduction network in ovarian cancer cells and its role in actomyosin dynamics, cell migration and entosis

Ojasalu¹,

Lieber²,

Sokòl³

et al. 2023

Theranostics

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Lysophosphatidic acid (LPA) species accumulate in the ascites of ovarian high-grade serous cancer (HGSC) and are associated with short relapse-free survival. LPA is known to support metastatic spread of cancer cells by activating a multitude of signaling pathways via G-protein-coupled receptors of the LPAR family. Systematic unbiased analyses of the LPA-regulated signal transduction network in ovarian cancer cells have, however, not been reported to date. Methods: LPA-induced signaling pathways were identified by phosphoproteomics of both patient-derived and OVCAR8 cells, RNA sequencing, measurements of intracellular Ca 2+ and cAMP as well as cell imaging. The function of LPARs and downstream signaling components in migration and entosis were analyzed by selective pharmacological inhibitors and RNA interference. Results: Phosphoproteomic analyses identified > 1100 LPA-regulated sites in > 800 proteins and revealed interconnected LPAR1, ROCK/RAC, PKC/D and ERK pathways to play a prominent role within a comprehensive signaling network. These pathways regulate essential processes, including transcriptional responses, actomyosin dynamics, cell migration and entosis. A critical component of this signaling network is MYPT1, a stimulatory subunit of protein phosphatase 1 (PP1), which in turn is a negative regulator of myosin light chain 2 (MLC2). LPA induces phosphorylation of MYPT1 through ROCK (T853) and PKC/ERK (S507), which is majorly driven by LPAR1. Inhibition of MYPT1, PKC or ERK impedes both LPA-induced cell migration and entosis, while interference with ROCK activity and MLC2 phosphorylation selectively blocks entosis, suggesting that MYPT1 figures in both ROCK/MLC2-dependent and -independent pathways. We finally show a novel pathway governed by LPAR2 and the RAC-GEF DOCK7 to be indispensable for the induction of entosis. Conclusion: We have identified a comprehensive LPA-induced signal transduction network controlling LPA-triggered cytoskeletal changes, cell migration and entosis in HGSC cells. Due to its pivotal role in this network, MYPT1 may represent a promising target for interfering with specific functions of PP1 essential for HGSC progression.

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Section: Discussionsupporting

confidence: 91%

“…8 E and 9 A). These observations may be clinically significant in view of the reported overexpression of DOCK7 in OC 122 and the inverse association of MYPT1 expression with HGSC survival ( Fig. S13 ).…”

Section: Discussionmentioning

confidence: 76%

The lysophosphatidic acid-regulated signal transduction network in ovarian cancer cells and its role in actomyosin dynamics, cell migration and entosis

Ojasalu¹,

Lieber²,

Sokòl³

et al. 2023

Theranostics

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“…It has been reported that RPA1 phosphorylation upon RS decreases the ubiquitination of chromatin-loaded RPA1, leading to an accumulation of RPA1 on stalled replication forks. This helps the DNA-binding domains of RPA2 to bind with RPA1-coated ssDNA, thus contributing to increased RPA2 binding stability (85). Loss of RPA accelerates fork breakage, whereas overexpression of RPA is sufficient to delay a "replication catastrophe" (86).…”

Section: Rpamentioning

confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress via increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.

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“…More recently, it was shown that Dock7 was essential for the survival of ovarian cancer cells after DNA damage and replication stress induced by chemotherapy. Gao, et al showed Dock7 activated Cdc42 and Rac in the nucleus to ensure proper replication stress response through the stimulation of the serine/threonine protein kinase Pak1 69 . Here, we highlight an important new role for Dock7, where it potentiates AKT activity within a distinct mTOR signaling complex to maintain a malignant phenotype and cell survival during stresses like those observed within the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

A multiprotein signaling complex sustains AKT and mTOR/S6K activity necessary for the survival of cancer cells undergoing stress

Teran

Zanotelli

Lin

et al. 2023

Preprint

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Cancer cells, both within a developing tumor and during metastatic spread, encounter many stresses that require adaptive mechanisms to survive and maintain malignant progression. Here we describe a signaling complex involving the small GTPase Cdc42 and Dock7, a Cdc42/Rac GEF and unique Cdc42-effector, that has a previously unappreciated role in regulating AKT, mTOR, and other mTOR signaling and regulatory partners including the TSC1/TCS2 complex and S6K during serum starvation. Dock7 is highly expressed in triple-negative breast cancers and is essential for the malignant properties in nutrient-deprived growth conditions of several cancer cell lines. We find that Dock7 interacts with phosphorylated AKT to maintain a low, but critical activation of a rapamycin-sensitive and Raptor-independent mTORC1-like activity required for survival during nutrient stress. Following the knock-out of Dock7 from cancer cells, interactions between AKT and the phosphatase PHLPP increased while phosphorylation of AKT at Ser473 decreased, suggesting Dock7 protects AKT from dephosphorylation. The DHR1 domain of Dock7, previously of unknown function, is responsible for maintaining AKT Ser473 phosphorylation during serum starvation through an interaction requiring its C2-like motif. Together, these findings indicate that Dock7 protects and maintains the phosphorylation of AKT to sustain a tonic mTOR/S6K activity in cancer cells necessary for their resistance to anoikis and to prevent them from undergoing apoptosis during stressful conditions.

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DOCK7 protects against replication stress by promoting RPA stability on chromatin

Cited by 13 publications

References 58 publications

The lysophosphatidic acid-regulated signal transduction network in ovarian cancer cells and its role in actomyosin dynamics, cell migration and entosis

The lysophosphatidic acid-regulated signal transduction network in ovarian cancer cells and its role in actomyosin dynamics, cell migration and entosis

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

A multiprotein signaling complex sustains AKT and mTOR/S6K activity necessary for the survival of cancer cells undergoing stress

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