Cdc7-Dbf4-mediated phosphorylation of HSP90-S164 stabilizes HSP90-HCLK2-MRN complex to enhance ATR/ATM signaling that overcomes replication stress in cancer

Cheng, An; Fan, Chi-Chen; Lo, Yu-Kang; Kuo, Cheng-Liang; Wang, Hui‐Chun; Lien, I-Hsin; Lin, Shu‐Yu; Chen, Chung–Hsing; Jiang, Shih Sheng; Chang, I–Shou; Juan, Hsueh‐Fen; Lyu, Ping‐Chiang; Lee, Alan Yueh‐Luen

doi:10.1038/s41598-017-17126-2

Cited by 21 publications

(19 citation statements)

References 78 publications

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“…CDC7 has already been reported to influence MRE11 activity through phosphorylation of the HSP90 chaperone, thus stabilizing a ATR–HSP90–HCLK2–MRE11 complex . Based on our data, it is tempting to speculate that CDC7 may regulate MRE11‐dependent processes through direct phosphorylation, promoting MRE11 nuclease activity and, in the long range, its retention at replication factories.…”

Section: Discussionsupporting

confidence: 58%

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage

et al. 2020

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The CDC7 kinase is essential for the activation of DNA replication origins and has been implicated in the replication stress response. Using a highly specific chemical inhibitor and a chemical genetic approach, we now show that CDC7 activity is required to coordinate multiple MRE11-dependent processes occurring at replication forks, independently from its role in origin firing. CDC7 localizes at replication forks and, similarly to MRE11, mediates active slowing of fork progression upon mild topoisomerase inhibition. Both proteins are also retained on stalled forks, where they promote fork processing and restart. Moreover, MRE11 phosphorylation and localization at replication factories are progressively lost upon CDC7 inhibition. Finally, CDC7 activity at reversed forks is required for their pathological MRE11-dependent degradation in BRCA2deficient cells. Thus, upon replication interference CDC7 is a key regulator of fork progression, processing and integrity. These results highlight a dual role for CDC7 in replication, modulating both initiation and elongation steps of DNA synthesis, and identify a key intervention point for anticancer therapies exploiting replication interference.

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Section: Discussionsupporting

confidence: 58%

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage

et al. 2020

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“…4 ). Since Cdc7-Dbf4 interacts with and phosphorylates HSP90-MRN complex to enhance ATR/ATM checkpoint signaling and DNA damage tolerance for the survival of cancer cells [ 41 ], the kinase inhibitor becomes an excellent anti-cancer agent that not only blocks DNA synthesis at the beginning but also sensitizes cancer cells to DNA damage agents. Although the resistance development of chemo- and radio-therapy, cis-diamminedichloroplatinum (II) (CDDP, cisplatin) and radiation are still widely used for the treatment of various solid tumors, including oral cancers [ 42 ].…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach

Cheng

Yang

et al. 2018

EBioMedicine

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BackgroundCdc7-Dbf4 is a conserved serine/threonine kinase that plays an important role in initiation of DNA replication and DNA damage tolerance in eukaryotic cells. Cdc7 has been found overexpressed in human cancer cell lines and tumor tissues, and the knockdown of Cdc7 expression causes an p53-independent apoptosis, suggesting that Cdc7 is a target for cancer therapy. Only a handful Cdc7 kinase inhibitors have been reported. All Cdc7 kinase inhibitors, including PHA-767491, were identified and characterized as ATP-competitive inhibitors. Unfortunately, these ATP-competitive Cdc7 inhibitors have no good effect on clinical trial.MethodsHere, we have developed a novel drug-screening platform to interrupt the interaction between Cdc7 and Dbf4 based on Renilla reniformis luciferase (Rluc)-linked protein-fragment complementation assay (Rluc-PCA). Using drug repositioning approach, we found several promising Cdc7 inhibitors for cancer therapy from a FDA-approved drug library.FindingsOur data showed that dequalinium chloride and clofoctol we screened inhibit S phase progression, accumulation in G2/M phase, and Cdc7 kinase activity. In addition, in vivo mice animal study suggests that dequalinium chloride has a promising anti-tumor activity in oral cancer. Interestingly, we also found that dequalinium chloride and clofoctol sensitize the effect of platinum compounds and radiation due to synergistic effect. In conclusion, we identified non-ATP-competitive Cdc7 kinase inhibitors that not only blocks DNA synthesis at the beginning but also sensitizes cancer cells to DNA damage agents.InterpretationThe inhibitors will be a promising anti-cancer agent and enhance the therapeutic effect of chemotherapy and radiation for current cancer therapy.FundThis work was supported by grants from the Ministry of Science and Technology, Ministry of Health and Welfare, and National Health Research Institutes, Taiwan.

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“…This may reflect an overlapping regulatory function between Cdc7 and ATM/ATR in replication fork machinery under replication stress. Certain studies [ 45 – 47 ] also confirm this phenomenon. Furthermore, Montagnoli et al demonstrated that MCM2 phosphorylation at Ser-41 (putative CDK-dependent site) and Ser-139 (putative CK2-dependent site) were not affected by reducing Cdc7 [ 24 ].…”

Section: Phosphorylation Of Mcms By Cdc7mentioning

confidence: 63%

Role of MCM2–7 protein phosphorylation in human cancer cells

Fei

2018

Cell Biosci

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A heterohexameric complex composed of minichromosome maintenance protein 2–7 (MCM2–7), which acts as a key replicative enzyme in eukaryotes, is crucial for initiating DNA synthesis only once per cell cycle. The MCM complex remains inactive through the G1 phase, until the S phase, when it is activated to initiate replication. During the transition from the G1 to S phase, the MCM undergoes multisite phosphorylation, an important change that promotes subsequent assembly of other replisome members. Phosphorylation is crucial for the regulation of MCM activity and function. MCMs can be phosphorylated by multiple kinases and these phosphorylation events are involved not only in DNA replication but also cell cycle progression and checkpoint response. Dysfunctional phosphorylation of MCMs appears to correlate with the occurrence and development of cancers. In this review, we summarize the currently available data regarding the regulatory mechanisms and functional consequences of MCM phosphorylation and seek the probability that protein kinase inhibitor can be used therapeutically to target MCM phosphorylation in cancer.

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Cdc7-Dbf4-mediated phosphorylation of HSP90-S164 stabilizes HSP90-HCLK2-MRN complex to enhance ATR/ATM signaling that overcomes replication stress in cancer

Cited by 21 publications

References 78 publications

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage

CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage

Identification of Novel Cdc7 Kinase Inhibitors as Anti-Cancer Agents that Target the Interaction with Dbf4 by the Fragment Complementation and Drug Repositioning Approach

Role of MCM2–7 protein phosphorylation in human cancer cells

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