CHK1 monitors spindle assembly checkpoint and DNA damage repair during the first cleavage of mouse early embryos

Ju, Jia-Qian; Li, Xiaohan; Pan, Meng-Hao; Xu, Yao; Sun, Ming‐Hong; Xu, Yuping; Sun, Shao‐Chen

doi:10.1111/cpr.12895

Cited by 13 publications

(18 citation statements)

References 45 publications

(87 reference statements)

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“…Thus, these results demonstrate that CHK1 is an important protein in SAC function. Without its presence, the integrity of the segregation mechanism is compromised and its function in DDR, supporting the dual role of this protein in both mechanisms ( Ju et al, 2020 ).…”

Section: A Collaborative Work Between Dna Damage and Spindle Assembly Checkpoint Proteinsmentioning

confidence: 82%

Mitotic and DNA Damage Response Proteins: Maintaining the Genome Stability and Working for the Common Good

Luna-Maldonado

Andonegui-Elguera

Díaz‐Chávez

et al. 2021

Front. Cell Dev. Biol.

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Cellular function is highly dependent on genomic stability, which is mainly ensured by two cellular mechanisms: the DNA damage response (DDR) and the Spindle Assembly Checkpoint (SAC). The former provides the repair of damaged DNA, and the latter ensures correct chromosome segregation. This review focuses on recently emerging data indicating that the SAC and the DDR proteins function together throughout the cell cycle, suggesting crosstalk between both checkpoints to maintain genome stability.

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Section: A Collaborative Work Between Dna Damage and Spindle Assembly Checkpoint Proteinsmentioning

confidence: 82%

Mitotic and DNA Damage Response Proteins: Maintaining the Genome Stability and Working for the Common Good

Luna-Maldonado

Andonegui-Elguera

Díaz‐Chávez

et al. 2021

Front. Cell Dev. Biol.

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“…MTs recruit trafficking proteins to repair aberrant DNA, leading to G1 phase arrest ( Lottersberger et al, 2015 ). Previous studies have shown that 7HF inhibits DNA Top I activity; 7HF may affect pre-replicative stress or single-stranded DNA break in the G1 phase arrest by upregulating Chk1 via Ataxia-Telangectasia and Rad3 related (ATR) kinase signaling ( Champoux, 2001 ; Ju et al, 2020 ; Petsalaki & Zachos, 2020 ; Uppatanpreecha, 2009 ). Chk1 is a key downstream regulator of ATR response and is phosphorylated by ATR at Ser345 ( Ju et al, 2020 ; Petsalaki & Zachos, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Anticancer mechanism of 7-α-hydroxyfrullanolide on microtubules and computational prediction of its target binding in triple-negative breast cancer cells

Chimplee

Smythe

Tipmanee

et al. 2022

PeerJ

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Background Triple-negative breast cancer (TNBC) responds poorly to the available drugs; thus, the mortality rate associated with TNBC remains high. 7-α-Hydroxyfrullanolide (7HF) possesses anticancer properties and arrests cells in the G2/M-phase via modulation of several proteins involved in the G2/M-phase transition, as well as the mitotic checkpoint in MDA-MB-468 (TNBC) cells. Microtubules (MTs) dynamically regulate cell division in the G2/M phase and are related to cancer cell stress response. However, antimitotic drug cytotoxicity to multiple cancer resistance developed in response to drugs are obstacles faced to date. Here, the activity and mechanism via which 7HF controls MTs dynamics was investigated in MDA-MB-468 cells. Methods 7HF uptake by MDA-MB-468 cells was assessed using spectrophotometry. The drug-like properties of 7HF were predicted using the Swiss-absorption, distribution, metabolism, and excretion (ADME) webtool. Then, the effect of 7HF treatment (6, 12, and 24 µM) on the dynamic arrangement of MTs was assessed for 1, 12, and 24 h using indirect immunofluorescence. Polymerization of α- and β-tubulin was assessed using different 7HF concentrations in a cell-free system for 1 h. Cell proliferation assay with bromodeoxyuridine plus propidium iodide staining and flow cytometry was performed at different 7HF concentrations and time points. The mechanism of action was assessed by detecting the expression of proteins, including Bub3, cyclin B1, p-Cdk1 (Tyr15), Rb, p-Rb (Ser780), Chk1, p-Chk1 (Ser345), Chk2, p-Chk2 (Ser516), and p-H2AX (Ser139), using western blotting. Molecular docking was used to predict the molecular interactions between 7HF and tubulins in MTs. Results We observed that 7HF was able to enter the MDA-MB-468 cells. The ADME webtool analysis predicted that it possesses the high passive permeation and gastrointestinal absorption properties of drugs. Various concentrations of 7HF disrupted the dynamic arrangement of spindle MTs by causing radial spindle array shrinkage and expansion of fibrous spindle density and radial array lengths in a time-dependent manner. 7HF reduced polymerization of α-, β-tubulin in dose-dependent manner. 7HF also triggered DNA damage response by inducing G2/M and G1 phase arrests in a concentration and time-dependent manner, which occurred due to the upregulation of Bub3, Chk1, p-Chk1 (Ser345), p-Cdk1 (Tyr15), and cyclin B1. According to molecular docking analysis, 7HF preferred to bind to β-tubulin over α-tubulin. The lactone, ketone, and hydroxyl groups of 7HF supported the 7HF-tubulin interactions. Hydrogen bonding with a hydrocarbon ring and salt bridge attractive forces were responsible for the binding versatility of 7HF. Conclusions This is the first study to investigate the molecular mechanism, MTs interacting sites, and the internalization and drug-like properties of 7HF in TNBC cells. The findings will be useful for developing 7HF-based treatment for patients with TNBC.

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“…The results showed that PPT exposure could lead to an increase in early embryonic γ-H2A.X in mice, indicating the occurrence of DNA damage in embryos. The effects of other environmental factors on the DNA damage in oocytes were widely reported, for example, HT-2 toxin exposure could induce DNA damage in mouse early embryos (Zhang et al, 2019), and this might be due to the defects of cell cycle factors, such as CHK1, since the disruption of these factors all could induce DNA damage in the early embryos (Ju et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Podophyllotoxin Exposure Causes Spindle Defects and DNA Damage-Induced Apoptosis in Mouse Fertilized Oocytes and Early Embryos

Liao

Wei

et al. 2020

Front. Cell Dev. Biol.

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Podophyllotoxin (PPT) is a kind of lignans extracted from the roots and stems of the genus Podophyllum from the tiller family, and it has been widely used in the treatment of condyloma acuminatum, multiple superficial epithelioma in the clinics. However, PPT has been reported to be toxic and can cause liver defects and other organ poisoning. In addition, emerging evidences also indicate that PPT has reproductive toxicity and causes female reproduction disorders. In this study, we used fertilized oocytes and tried to explore the effects of PPT on the early embryonic development with the mouse model. The results showed that exposure to PPT had negative effects on the cleavage of zygotes. Further analysis indicated that PPT could disrupt the organization of spindle and chromosome arrangement at the metaphase of first cleavage. We also found that PPT exposure to the zygotes induced excessive reactive oxygen species (ROS), suggesting the occurrence of oxidative stress. Moreover, in the PPT-exposed embryos, there was positive γH2A.X and Annexin-V signals, indicating that PPT induced embryonic DNA damage and early apoptosis. In conclusion, our results suggested that PPT could affect spindle formation and chromosome alignment during the first cleavage of mouse embryos, and its exposure induced DNA damage-mediated oxidative stress which eventually led to embryonic apoptosis, indicating the toxic effects of PPT on the early embryo development.

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CHK1 monitors spindle assembly checkpoint and DNA damage repair during the first cleavage of mouse early embryos

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 13 publications

References 45 publications

Mitotic and DNA Damage Response Proteins: Maintaining the Genome Stability and Working for the Common Good

Mitotic and DNA Damage Response Proteins: Maintaining the Genome Stability and Working for the Common Good

Anticancer mechanism of 7-α-hydroxyfrullanolide on microtubules and computational prediction of its target binding in triple-negative breast cancer cells

Podophyllotoxin Exposure Causes Spindle Defects and DNA Damage-Induced Apoptosis in Mouse Fertilized Oocytes and Early Embryos

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