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Results for “Cell Cycle Checkpoints”

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At least 19 recordsLinked to original sources

PubMed2026

Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.

UNLABELLED: Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical cancer models. Clinically, the Notch ligand JAG1 was upregulated in patients with recurrent high-grade glioma treated with the oHSV CAN-3110 and correlated with poor prognosis. To better understand endogenous JAG1-mediated signaling in glioma cells and tumor-associated macrophages (TAM), we engineered a JAG1-antagonizing oHSV (OD-0J1) and interrogated its impact on cancer and myeloid cells in the TME. OD-0J1 antagonized JAG1-mediated Notch signaling and suppressed tumor growth in athymic nude and humanized mice, an effect reliant on Notch signaling in tumor cells. Kinome profiling revealed that OD-0J1 treatment suppressed CDK1, resulting in activation of the G2-M cell cycle checkpoint. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62, and autophagosome accumulation and senescence-associated β-galactosidase activity. OD-0J1-induced senescence resulted in increased production of inflammatory chemokines and damage-associated molecular patterns (DAMP), such as IL1β, HMGB1, and extracellular ATP. Coculturing macrophages with OD-0J1-infected tumor cells led to stimulation of chemotactic and proinflammatory pathways, as well as increased Fc receptor activation. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OD-0J1 treatment. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the antitumor therapeutic efficacy of OD-0J1. SIGNIFICANCE: Leveraging JAG1 antagonism in the context of oncolytic virotherapy rewires macrophage polarization within the tumor microenvironment, which has wide implications for sensitizing tumors to antibodies, senolytic agents, and BiTE therapies.

Humans↗

PubMed2025

FRET-FLIM for the Study of Protein-Protein Interactions Underpinning Mitosis Checkpoints.

Cell division is a key cellular process that ensures the continuation of life on Earth. In order to protect the genetic integrity of organisms, cell division must happen accurately, ensuring each daughter cell receives a complete copy of the original genome. The accuracy of this process is, in part, preserved by various cell cycle checkpoints. These checkpoints rely on the physical interactions of their components to ensure proper function. The spindle assembly checkpoint (SAC), for example, produces an inhibitory complex of BUBR1-BUB3 and MAD2 bound to CDC20. Many of these cell cycle checkpoint components have been identified in plants, but it has not yet been established whether plants have a mitotic checkpoint architecture that is similar to mammalian cells. To understand the function of plant cell cycle homologues, it is imperative to characterize their interactions in vivo. FRET-FLIM (Förster resonance energy transfer-fluorescence lifetime imaging microscopy), is a rapidly expanding technique that can be used to rapidly and simply characterize protein-protein interactions.

Fluorescence Resonance Energy Transfer↗

PubMed2026

WEE1 kinase in cancer: Molecular mechanisms and inhibitor insights.

WEE1 kinase is a main regulator of the G2/M cell cycle checkpoint. It plays an important role in maintaining genomic stability by inhibiting CDK1 through a phosphorylation process at Tyr15. WEE1 is found to be overexpressed in several cancers and also act as a protective mechanism that allows cancer cells to repair DNA damage and survive under replicative stress. So, pharmacological inhibition of WEE1 has emerged as a promising therapeutic strategy. Many conventional chemotherapeutic agents act by inducing DNA damage, so it enables the activation of WEE1 in cancer cells to arrest the cell cycle and repair this damage by preventing cell death. Inhibition of WEE1 disrupts this protective checkpoint, which ultimately leads to mitotic catastrophe. Therefore, targeting WEE1 represents a promising and rational therapeutic approach, mainly in tumors with TP53 mutations. We have comprehensively discussed the structural features of WEE1, its regulation in DNA damage response, epigenetic control, and its role in cancer progression. We have also summarized the clinical development of major WEE1 inhibitors such as adavosertib, azenosertib (ZN-c3), and Debio 0123. Moreover, recently synthesized small-molecule inhibitors are also discussed with special focus on structure-activity relationship (SAR) insights, dual-target inhibitors, and PROTACs and molecular glue-based degraders. Two compounds, 8 and 11, were found to be the most potent WEE1 inhibitors with excellent enzymatic inhibition. This explains the importance of rational scaffold optimization and electron-withdrawing group insertion for enhanced activity. Overall, this review serves as a valuable reference for medicinal chemists in the development of next-generation WEE1 inhibitors. See also the graphical abstract(Fig. 1).

WEE1 kinase↗

PubMed2026

Functions and mechanisms of BRCA1 in early embryonic development.

Breast Cancer Gene 1 (BRCA1) is a critical regulator of genome integrity whose dysfunction greatly increases lifetime risk of breast and ovarian cancers. While BRCA1 has been extensively studied in the contexts of adult biology and cancer, its diverse functions, including homologous recombination-mediated DNA repair, cell cycle checkpoint activation, protein ubiquitination, and transcriptional regulation, have many underexplored implications. In early embryonic development, the maternal-to-zygotic transition (MZT) and subsequent developmental processes place extraordinary demands on DNA replication fidelity, cell cycle regulation, transcriptional activation, and chromatin remodeling. These critical processes overlap strikingly with canonical functions of BRCA1, yet its function in early development is poorly characterized. In this review, we investigate BRCA1 conservation across species and connect its well-established functions to findings from developmental studies to assess its role in development. We highlight evidence of BRCA1 mitigating genome integrity loss from diverse sources, maintaining the proliferative activity needed for successful germ layer formation and early tissue morphogenesis, and regulating transcription and epigenetic modifications. Together, this synthesis supports a model where BRCA1 acts as a multi-functional and dynamic regulator of early embryogenesis. Building on this, we propose outstanding questions that could further illuminate these developmental roles. Characterization of BRCA1 in early development may not only provide important insight into the origin and progression of cancer susceptibility but may also elucidate fundamental mechanisms shaping early development.

BRCA1 Protein↗

PubMed2025

The genome of the polyextremophilic yeast, Naganishia friedmannii, reveals adaptations involved in stress response pathways, carbohydrate metabolism expansion, and a limited DNA repair repertoire.

Here we report the draft genome sequence of Naganishia friedmannii (formerly Cryptococcus friedmannii) isolate, a Basidiomycota yeast commonly found in some of the most extreme environments of the Earth's cryosphere. We isolated N. friedmannii strain Llullensis from soils at 6000 m above sea level on Volcán Llullaillaco, Argentina. The genome was 22.2 Mb with 6251 identified protein coding genes. Proteins known to be associated with thermal, osmotic, and radiation stress were identified in the genome. Comparative analysis with seven other Naganishia genomes revealed unique features underlying its polyextremophilic lifestyle. Naganishia friedmannii showed an expansion of genes involved in breaking down plant-derived carbohydrates, supporting the hypothesis that it survives at high elevations by metabolizing wind-deposited organic matter. Surprisingly, many genes involved in cell-cycle checkpoints and DNA repair were missing, as in several other Naganishia species. This extensive loss may be adaptive in extreme environments prone to abiotic stress, where a high mutation rate could generate advantageous traits, and reduced cell-cycle control may allow for faster reproduction that would be advantageous for rapid growth during brief periods of soil wetting following rare snow events.

Carbohydrate Metabolism↗

PubMed1992

A fundamental role for cell cycle regulation in the chemosensitivity of cancer cells?

The majority of clinically effective anticancer drugs inhibit some aspect of the machinery responsible for DNA replication and chromosome segregation. Drug action also arrests cells at defined points in the cell cycle called checkpoints. These checkpoints ensure that subsequent cell cycle events are inhibited until the inflicted damage is repaired. The fidelity of checkpoint control and susceptibility of cells to apoptosis while repair is underway may be important factors in the success of chemotherapy. We discuss these concepts and focus particularly on possible applications to improved antitumor therapy with DNA damaging agents.

Antineoplastic Agents↗

PubMed2014

The N-terminus of Mcm10 is important for interaction with the 9-1-1 clamp and in resistance to DNA damage.

Accurate replication of the genome requires the evolutionarily conserved minichromosome maintenance protein, Mcm10. Although the details of the precise role of Mcm10 in DNA replication are still debated, it interacts with the Mcm2-7 core helicase, the lagging strand polymerase, DNA polymerase-α and the replication clamp, proliferating cell nuclear antigen. Loss of these interactions caused by the depletion of Mcm10 leads to chromosome breakage and cell cycle checkpoint activation. However, whether Mcm10 has an active role in DNA damage prevention is unknown. Here, we present data that establish a novel role of the N-terminus of Mcm10 in resisting DNA damage. We show that Mcm10 interacts with the Mec3 subunit of the 9-1-1 clamp in response to replication stress evoked by UV irradiation or nucleotide shortage. We map the interaction domain with Mec3 within the N-terminal region of Mcm10 and demonstrate that its truncation causes UV light sensitivity. This sensitivity is not further enhanced by a deletion of MEC3, arguing that MCM10 and MEC3 operate in the same pathway. Since Rad53 phosphorylation in response to UV light appears to be normal in N-terminally truncated mcm10 mutants, we propose that Mcm10 may have a role in replication fork restart or DNA repair.

Cell Cycle Proteins↗

PubMed2012

The nontoxic cell cycle modulator indirubin augments transduction of adeno-associated viral vectors and zinc-finger nuclease-mediated gene targeting.

Parameters that regulate or affect the cell cycle or the DNA repair choice between non-homologous end-joining and homology-directed repair (HDR) are excellent targets to enhance therapeutic gene targeting. Here, we have evaluated the impact of five cell-cycle modulating drugs on targeted genome engineering mediated by DNA double-strand break (DSB)-inducing nucleases, such as zinc-finger nucleases (ZFNs). For a side-by-side comparison, we have established four reporter cell lines by integrating a mutated EGFP gene into either three transformed human cell lines or primary umbilical cord-derived mesenchymal stromal cells (UC-MSCs). After treatment with different cytostatic drugs, cells were transduced with adeno-associated virus (AAV) vectors that encode a nuclease or a repair donor to rescue EGFP expression through DSB-induced HDR. We show that transient cell-cycle arrest increased AAV transduction and AAV-mediated HDR up to six-fold in human cell lines and ten-fold in UC-MSCs, respectively. Targeted gene correction was observed in up to 34% of transduced cells. Both the absolute and the relative gene-targeting frequencies were dependent on the cell type, the cytostatic drug, the vector dose, and the nuclease. Treatment of cells with the cyclin-dependent kinase inhibitor indirubin-3'-monoxime was especially promising as this compound combined high stimulatory effects with minimal cytotoxicity. In conclusion, indirubin-3'-monoxime significantly improved AAV transduction and the efficiency of AAV/ZFN-mediated gene targeting and may thus represent a promising compound to enhance DSB-mediated genome engineering in human stem cells, such as UC-MSCs, which hold great promise for future clinical applications.

Blotting, Western↗

PubMed2020

Human NK cell deficiency as a result of biallelic mutations in MCM10.

Human natural killer cell deficiency (NKD) arises from inborn errors of immunity that lead to impaired NK cell development, function, or both. Through the understanding of the biological perturbations in individuals with NKD, requirements for the generation of terminally mature functional innate effector cells can be elucidated. Here, we report a cause of NKD resulting from compound heterozygous mutations in minichromosomal maintenance complex member 10 (MCM10) that impaired NK cell maturation in a child with fatal susceptibility to CMV. MCM10 has not been previously associated with monogenic disease and plays a critical role in the activation and function of the eukaryotic DNA replisome. Through evaluation of patient primary fibroblasts, modeling patient mutations in fibroblast cell lines, and MCM10 knockdown in human NK cell lines, we have shown that loss of MCM10 function leads to impaired cell cycle progression and induction of DNA damage-response pathways. By modeling MCM10 deficiency in primary NK cell precursors, including patient-derived induced pluripotent stem cells, we further demonstrated that MCM10 is required for NK cell terminal maturation and acquisition of immunological system function. Together, these data define MCM10 as an NKD gene and provide biological insight into the requirement for the DNA replisome in human NK cell maturation and function.

Alleles↗

PubMed2026

[BRCA1 Gene's Mutations And Hereditary Breast Cancer: Genetic, Biological, And Clinical Aspects].

INTRODUCTION: Hereditary breast cancer accounts for approximately 5 to 10% of all breast cancer cases. Mutations in the BRCA1 gene, which plays a central role in DNA repair and cell cycle regulation, are the main cause of these familial forms and are strongly associated with aggressive subtypes, particularly triple-negative breast cancer. METHODS: A narrative literature review was conducted using biomedical databases (PubMed, Scopus, Web of Science, Google Scholar) between January 2024 and June 2025. Eligible publications addressed the genetic, biological, epidemiological, and clinical aspects of BRCA1 in hereditary breast cancer. RESULTS: BRCA1 ensures genomic stability through its roles in DNA repair, cell cycle checkpoints, and transcriptional regulation. Most mutations are truncating or missense variants, with some reported as founder mutations (e.g., c.68_69delAG, c.5266dupC, 943ins10). Women carrying germline BRCA1 mutations have an estimated lifetime risk of 56-87% of developing breast cancer, with a strong association with aggressive molecular subtypes, especially triple-negative breast cancer. CONCLUSION: A comprehensive understanding of BRCA1 mutations is crucial to enhance prevention, screening, and personalized management of hereditary breast cancer. In low-resource settings, the integration of genetic testing and counseling remains a major challenge and a public health priority to reduce disparities in cancer care.

Humans↗

PubMed2026

Cumulus cells enhance oocyte genomic quality control by promoting DNA damage-induced meiotic arrest.

Cumulus cells are known to maintain oocyte arrest at prophase I through gap junction-mediated cAMP signalling, but their role after meiotic resumption remains unclear. Here, we show that cumulus cells enhance oocyte genomic quality control by sensitizing mouse oocytes to DNA damage-induced meiotic arrest. Time-lapse imaging of SiR-tubulin-labelled spindles revealed that oocytes from cumulus-oocyte complexes (COCs) matured faster than denuded oocytes (DOs). Upon mild DNA damage induced by low-dose etoposide, COC oocytes arrested at metaphase I, whereas DOs completed maturation despite similar levels of DNA lesions. This arrest required spindle assembly checkpoint (SAC) activity, as reversine rescued polar body extrusion and BubR1 and Mad2 were elevated in COCs but not DOs. Disruption of gap junctions or inhibition of mTOR signalling abolished the checkpoint response. Notably, cumulus cells did not enhance oocyte response to minor spindle perturbations. These findings reveal a previously unrecognized role of cumulus cells in mediating DNA damage-induced SAC activation, providing post-GVBD genomic surveillance beyond prophase I arrest.

Animals↗

PubMed2026

LiCl induces GSK-3β mediated autophagy, DNA damage, and cell cycle arrest in HPV driven cervical cancer cells.

High-risk HPV infections induce cervical cancer progression by disrupting cellular homeostasis and survival pathways, including autophagy. Targeting autophagy represents a promising therapeutic strategy. Lithium chloride (LiCl), extensively studied for its neuroprotective properties, can be investigated for its potential anticancer effects in HPV-driven cervical cancer cells. Treatment with 30 mM LiCl induced significant phosphorylation of glycogen synthase kinase-3β (GSK-3β) at Ser9, inducing functional inhibition and downstream signal alterations. This modulation of GSK-3β activity compromised genomic integrity, validated by increased double strand DNA breaks, increased oxidative and cellular stress, and reduced antioxidant enzyme activity. Consequently, LiCl treated cells exhibited significant G2/M phase arrest, indicating disruption in cell cycle progression. Interestingly, the observed cytotoxicity occurred independently of classical apoptotic pathways, suggesting the activation of alternative cell death mechanisms. Mechanistic studies revealed a robust autophagic flux, with GSK-3β mediated autophagy, validated through siRNA mediated knockdown experiments. These findings highlight a novel cytotoxic mechanism of LiCl and propose its potential repurposing from neurobiology to targeted cancer therapeutics.

Humans↗

PubMed2025

The Use of APC/C Antagonists to Promote Mitotic Catastrophe in Cancer Cells.

The multiprotein subunit E3 ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C) plays a key role in the control of mitosis progression. APC/C is the ultimate effector of the Spindle Assembly Checkpoint (SAC), the signaling system of higher organisms including the human that monitors the proper attachment of chromosomes to microtubules during cell division. Defects in this process result in genome instability, aneuploidy, premature aging, and cancer. APC/C roles in the SAC require its activation by the protein Cdc20. Interfering with APC/C activation by Cdc20 impairs APC/C substrate recognition, resulting in a delayed mitotic exit and eventually inducing cell death. This may be advantageous for the treatment of cancer and malignancies associated with SAC dysregulation. Here we describe a protocol to interfere with mitotic exit through the use of commercially available (Apcin, proTAME) as well as innovative small molecules we have developed that function as antagonists of APC/C activation by Cdc20. We show that the use of these molecules alone and in combination is effective to promote mitotic catastrophe and suppress cell expansion in 2D and 3D (spheroids) cancer cells of different tissue origin, including breast, cervical, and ovarian cancer.

Humans↗

PubMed2021

DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond.

Genome damage is a threat to all organisms. To respond to such damage, DNA damage responses (DDRs) lead to cell cycle arrest, DNA repair, and cell death. Many DDR components are highly conserved, whereas others have adapted to specific organismal needs. Immense progress in this field has been driven by model genetic organism research. This review has two main purposes. First, we provide a survey of model organism-based efforts to study DDRs. Second, we highlight how model organism study has contributed to understanding how specific DDRs are influenced by cell cycle stage. We also look forward, with a discussion of how future study can be expanded beyond typical model genetic organisms to further illuminate how the genome is protected.

Animals↗

PubMed2025

Generation of Cdc20 RNAi-Sensitive Cell Lines to Study Mitotic Exit.

Accurate mitotic progression ensures the fidelity of genome passage. Cdc20 is a key mitotic regulator. It promotes mitotic exit by activating the anaphase-promoting complex or cyclosome (APC/C) and monitors kinetochore-microtubule attachment through activating the spindle assembly checkpoint (SAC). Precise characterization of Cdc20 requires efficient depletion of endogenous Cdc20, which is extremely difficult to achieve by RNA interference (RNAi). This chapter describes the methodology to generate Cdc20 RNAi-sensitive cell lines with the help of CRISPR/Cas9 technology. These cell lines are highly sensitive to Cdc20 RNAi and provide a very useful tool for Cdc20 functionality investigation without the interference of endogenous Cdc20 protein. Similar strategy could be applied to other genes.

Cdc20 Proteins↗

PubMed2026

Senotypes define the diverse landscape of senescent cells.

Cellular senescence was initially defined in vitro as a stable cell-cycle arrest that occurs after repeated replication, but it is now recognized as a heterogeneous state shaped by cell type, species, senescence-inducing stress, tissue microenvironment and time. To organize this complexity, we propose the term 'senotype' to classify senescent cells by their inputs, molecular features and functional effects. We outline a practical framework incorporating: (1) cell identity and context; (2) inducing mechanism; (3) temporal stage; (4) multimodal molecular and structural features; and (5) physiological or pathological functions. Experimentally defined senotypes can serve as references for interpreting tissue-derived senotypes, where parameters may be incomplete. Senotypes should be anchored in combinations of core hallmarks (that is, durable cell-cycle arrest, altered secretory profiles, macromolecular or organelle damage, disrupted homeostasis) rather than single markers. Advances in single-cell, spatial, proteomic and computational methods enable rigorous senotype characterization, improving consistency and accelerating development of targeted senotherapeutics.

Cellular Senescence↗

PubMed2025

From Worms to Tumors: Conserved Strategies of Cellular Arrest and Survival Governing Dormancy.

The recurrence of metastatic lesions months to years after the treatment of primary cancers remains a major contributor to cancer-related mortality, highlighting the need to better understand the mechanisms that govern dormancy and dormancy reawakening. A major hurdle is the lack of adequate in vitro and in vivo models to dissect the complex cascades that trigger tumor cell dissemination, adoption of the dormant state, or tumor cell outgrowth in the new metastatic microenvironmental niche. However, many organisms use dormancy to survive stressful environments or periods of nutrient deprivation. Of these, the dauer state of the free-living nematode Caenorhabditis elegans has unparalleled characterization. In this study, we discuss the remarkable physiologic, signaling, genomic, and metabolic similarities between dormant cancer cells and C. elegans dauers, arguing for the use of dauers as a facile model to help dissect dormancy and reawakening pathways in cancer cells.

Animals↗

PubMed2025

Chromosome duplication causes premature aging via defects in ribosome quality control.

Down syndrome, caused by an extra copy of Chromosome 21, causes lifelong problems. One of the most common phenotypes among people with Down syndrome is premature aging, including early tissue decline, neurodegeneration, and shortened life span. Yet the reasons for premature systemic aging are a mystery and difficult to study in humans. Here we show that chromosome amplification in wild yeast also produces premature aging and shortens life span. Chromosome duplication disrupts nutrient-induced cell-cycle arrest, entry into quiescence, and cellular health during chronological aging, across genetic background and independent of which chromosome is amplified. Using a genomic screen, we discovered that these defects are due in part to aneuploidy-induced dysfunction in Ribosome Quality Control (RQC). We show that aneuploids entering quiescence display aberrant ribosome profiles, accumulate RQC intermediates, and harbor an increased load of protein aggregates compared to euploid cells. Although they maintain proteasome activity, aneuploids also show signs of ubiquitin dysregulation and sequestration into foci. Remarkably, inducing ribosome stalling in euploids produces similar aging phenotypes, while up-regulating limiting RQC subunits or poly-ubiquitin alleviates many of the aneuploid defects. We propose that the increased translational load caused by having too many mRNAs accelerates a decline in translational fidelity, contributing to premature aging.

Ribosomes↗