bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–03–02
eight papers selected by
Valentina Piano, Uniklinik Köln
  1. Emerging Roles for Transcription Factors During Mitosis.
  2. Polo-like kinase 1 maintains transcription and chromosomal accessibility during mitosis.
  3. The Role of p53 Mutations in Early and Late Response to Mitotic Aberrations.
  4. Mitotic transcription ensures ecDNA inheritance through chromosomal tethering.
  5. The functional organisation of the centromere and kinetochore during meiosis.
  6. The SETDB1-PC4-UPF1 post-transcriptional machinery controls periodic degradation of CENPF mRNA and maintains mitotic progression.
  7. Small Molecules Identified by an In Silico Docking Screen Targeting Anaphase-Promoting Complex/Cyclosome Subunit 1 (APC1) Potentiate Paclitaxel-Induced Breast Cancer Cell Death.
  8. PACS deficiency disrupts Golgi architecture and causes cytokinesis failures and seizure-like phenotype in Drosophila melanogaster.
  1. Cells. 2025 Feb 12. pii: 263. [Epub ahead of print]14(4):
    Emerging Roles for Transcription Factors During Mitosis.
    Samuel Flashner, Jane Azizkhan-Clifford.
      The genome is dynamically reorganized, partitioned, and divided during mitosis. Despite their role in organizing interphase chromatin, transcription factors were largely believed to be mitotic spectators evicted from chromatin during mitosis, only able to reestablish their position on DNA upon entry into G1. However, a panoply of evidence now contradicts this early belief. Numerous transcription factors are now known to remain active during mitosis to achieve diverse purposes, including chromosome condensation, regulation of the centromere/kinetochore function, and control of centrosome homeostasis. Inactivation of transcription factors during mitosis results in chromosome segregation errors, key features of cancer. Moreover, active transcription and the production of centromere-derived transcripts during mitosis are also known to play key roles in maintaining chromosomal stability. Finally, many transcription factors are associated with chromosomal instability through poorly defined mechanisms. Herein, we will review the emerging roles of transcription factors and transcription during mitosis with a focus on their role in promoting the faithful segregation of sister chromatids.
    Keywords:  aneuploidy; centromere; centrosome; chromosomal instability; chromosome condensation; chromosome segregation; genome instability; kinetochore; mitosis; transcription factor
    DOI:  https://doi.org/10.3390/cells14040263
  2. bioRxiv. 2025 Feb 16. pii: 2025.02.12.637959. [Epub ahead of print]
    Polo-like kinase 1 maintains transcription and chromosomal accessibility during mitosis.
    Zhouyuan Shen, Kristin Adams, Ryan Moreno, Robert Lera, Emily Kaufman, Jessica D Lang, Mark Burkard.
      Transcription persists at low levels in mitotic cells and plays essential roles in mitotic fidelity and chromosomal dynamics. However, the detailed regulatory network of mitotic transcription remains largely unresolved. Here, we report the novel role of Polo-like kinase 1 (Plk1) in maintaining mitotic transcription. Using 5-ethynyl uridine (5-EU) labeling of nascent RNAs, we found that Plk1 inhibition leads to significant downregulation of nascent transcription in prometaphase cells. Chromatin-localized Plk1 activity is required for transcription regulation and mitotic fidelity. Plk1 sustains global chromosomal accessibility in mitosis, especially at promoter and transcription start site (promoter-TSS) regions, facilitating transcription factor binding and ensuring proper transcriptional activity. We identified SMC4, a common subunit of condensin I and II, as a potential Plk1 substrate. Plk1 activity is fundamental to these processes across non-transformed and transformed cell lines, underscoring its critical role in cell cycle regulation. This study elucidates a novel regulatory mechanism of global mitotic transcription, advancing our understanding of cell cycle control.
    Significance Statement: Cells retain a low level of transcription during mitosis, while the regulatory network and specific contributions of mitotic transcription are not well understood.We identify Polo-like kinase 1 (Plk1) as a novel regulator of mitotic transcription, crucial for chromosome condensation, genome accessibility, and maintaining mitotic fidelity.This study enhances our understanding of Plk1's multifaceted role in mitotic progression, advancing cell cycle regulation knowledge, and informing new cancer therapies' development.
    DOI:  https://doi.org/10.1101/2025.02.12.637959
  3. Biomolecules. 2025 Feb 08. pii: 244. [Epub ahead of print]15(2):
    The Role of p53 Mutations in Early and Late Response to Mitotic Aberrations.
    Anna Hertel, Zuzana Storchová.
      Mutations in the TP53 gene and chromosomal instability (CIN) are two of the most common alterations in cancer. CIN, marked by changes in chromosome numbers and structure, drives tumor development, but is poorly tolerated in healthy cells, where developmental and tissue homeostasis mechanisms typically eliminate cells with chromosomal abnormalities. Mechanisms that allow cancer cells to acquire and adapt to CIN remain largely unknown. Tumor suppressor protein p53, often referred to as the "guardian of the genome", plays a critical role in maintaining genomic stability. In cancer, CIN strongly correlates with TP53 mutations, and recent studies suggest that p53 prevents the propagation of cells with abnormal karyotypes arising from mitotic errors. Furthermore, p53 dysfunction is frequent in cells that underwent whole-genome doubling (WGD), a process that facilitates CIN onset, promotes aneuploidy tolerance, and is associated with poor patient prognosis across multiple cancer types. This review summarizes current insights into p53's role in protecting cells from chromosome copy number alterations and discusses the implications of its dysfunction for the adaption and propagation of cancer cells.
    Keywords:  TP53; aneuploidy; chromosomal instability; chromosome missegregation; whole-genome doubling
    DOI:  https://doi.org/10.3390/biom15020244
  4. bioRxiv. 2025 Feb 16. pii: 2025.02.12.637945. [Epub ahead of print]
    Mitotic transcription ensures ecDNA inheritance through chromosomal tethering.
    Ashley Nichols, Roshan Norman, Yanyang Chen, Yujin Choi, Josefine Striepen, Eralda Salataj, Eleonore Toufektchan, Richard Koche, John Maciejowski.
      Extrachromosomal DNA (ecDNA) are circular DNA bodies that play critical roles in tumor progression and treatment resistance by amplifying oncogenes across a wide range of cancer types. ecDNA lack centromeres and are thus not constrained by typical Mendelian segregation, enabling their unequal accumulation within daughter cells and associated increases in copy number. Despite intrinsic links to their oncogenic potential, the fidelity and mechanisms of ecDNA inheritance are poorly understood. Here, we show that ecDNA are protected against cytosolic mis-segregation through mitotic clustering and by tethering to the telomeric and subtelomeric regions of mitotic chromosomes. ecDNA-chromosome tethering depends on BRD4 transcriptional co-activation and mitotic transcription of the long non-coding RNA PVT1 , which is co-amplified with MYC in colorectal and prostate cancer cell lines. Disruption of ecDNA-chromosome tethering through BRD4 inhibition, PVT1 depletion, or inhibiting mitotic transcription results in cytosolic mis-segregation, ecDNA reintegration, and the formation of homogeneously staining regions (HSRs). We propose that nuclear inheritance of ecDNA is facilitated by an RNA-mediated physical tether that links ecDNA to mitotic chromosomes and thus protects against cytosolic mis-segregation and chromosomal integration.
    DOI:  https://doi.org/10.1101/2025.02.12.637945
  5. Curr Opin Cell Biol. 2025 Feb 26. pii: S0955-0674(25)00024-9. [Epub ahead of print]94 102486
    The functional organisation of the centromere and kinetochore during meiosis.
    Lori B Koch, Adele L Marston.
      Meiosis generates gametes through a specialised cell cycle that reduces the genome by half. Homologous chromosomes are segregated in meiosis I and sister chromatids are segregated in meiosis II. Centromeres and kinetochores play central roles in instructing this specialised chromosome segregation pattern. Accordingly, kinetochores acquire meiosis-specific modifications. Here we contextualise recent highlights in our understanding of how centromeres and kinetochores direct the sorting of chromosomes into gametes via meiosis.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102486
  6. Cell Death Differ. 2025 Feb 27.
    The SETDB1-PC4-UPF1 post-transcriptional machinery controls periodic degradation of CENPF mRNA and maintains mitotic progression.
    Qimei Pan, Peng Luo, Yuntan Qiu, Kaishun Hu, Lehang Lin, Heyun Zhang, Dong Yin, Chunmeng Shi.
      Numerous genes exhibit periodic oscillations in mRNA expression, essential for orderly cell division. Mitosis-related mRNAs fluctuate cyclically from the G2 to M phase, primarily regulated by transcription factors. However, the role of post-transcriptional regulation in this process remains unclear. Here, we demonstrated a decrease in mRNA levels of centromere protein F (CENPF) from the early to late G2 phase. SETDB1-PC4-UPF1 serves as a crucial post-transcriptional machinery, orchestrating the periodic degradation of CENPF mRNA, ensuring balanced CENP expression, proper spindle assembly, and successful mitosis. In early G2, newly synthesized CENPF mRNAs accumulate and bind to PC4, leading to SETDB1-mediated PC4 dimethylation at K35. In late G2, dimethylated PC4 interacts with UPF1 to promote deadenylation-dependent degradation of CENPF mRNAs, forming a regulatory loop for CENP homeostasis. Elevated PC4 dimethylation in hepatocellular carcinoma, coupled with increased sensitivity to taxanes upon its inhibition, suggests promising therapeutic avenues. These findings suggest a post-transcriptional quality control mechanism regulating cyclic mitotic mRNA fluctuations, providing comprehensive insights into cell cycle gene regulation dynamics.
    DOI:  https://doi.org/10.1038/s41418-025-01465-z
  7. Molecules. 2025 Feb 14. pii: 895. [Epub ahead of print]30(4):
    Small Molecules Identified by an In Silico Docking Screen Targeting Anaphase-Promoting Complex/Cyclosome Subunit 1 (APC1) Potentiate Paclitaxel-Induced Breast Cancer Cell Death.
    Scott C Schuyler, Rythm Gupta, Tran Thi Bao Nguyen, Cheng-Ye Weng, Hsin-Yu Chen.
      Delaying mitotic cell cycle progression has been proposed as a strategy to potentiate the effects of anti-mitotic anti-cancer drugs that induce multipolar mitotic spindles. Toward this end, we have performed an in silico docking screen targeting anaphase-promoting complex/cyclosome subunit 1 (APC1) at a conserved 10-amino acid surface site that was modeled to interact via a single hydrogen bond with the essential mitotic anaphase-promoting complex/cyclosome (APC/C) co-factor cell division cycle 20 (CDC20). Five molecules were identified after screening 15,000 small molecules. As a secondary in cellulo bioactivity screening, MDA-MB-231 genomically unstable aneuploid breast cancer cells were exposed to each compound in the absence and presence of 10 nM paclitaxel or 1 nM eribulin, the likely clinically relevant doses of these drugs in these cells. Two of the five compounds, which share a common 2-(trifluoromethyl)quinazolin-4-amine chemical structure, induced elevated levels of cell death in combination with paclitaxel, as observed by fluorescence-activated cell sorting (FACS). These two compounds will now serve as a starting point for further optimization and target validation experiments and for additional in silico screens in search of other chemically related small molecules that display more potent but specific anti-cancer cell effects.
    Keywords:  anaphase-promoting complex subunit 1 (APC1); anaphase-promoting complex/cyclosome (APC/C); cancer; cell division; cell division cycle 20 (CDC20); docking
    DOI:  https://doi.org/10.3390/molecules30040895
  8. Open Biol. 2025 Feb;15(2): 240267
    PACS deficiency disrupts Golgi architecture and causes cytokinesis failures and seizure-like phenotype in Drosophila melanogaster.
    Anna Frappaolo, Gianluca Zaccagnini, Maria Giovanna Riparbelli, Gianni Colotti, Giuliano Callaini, Maria Grazia Giansanti.
      The PACS (phosphofurin acidic cluster sorting protein) proteins are membrane trafficking regulators, required for maintaining cellular homeostasis and preventing disease states. Mutations in human PACS1 and PACS2 cause human neurodevelopmental disorders, characterized by epileptic seizures and neurodevelopmental delay. In vertebrates, functional analysis of PACS proteins is complicated by the presence of two paralogues which can compensate for the loss of each other. Here, we characterize the unique fly homologue of human PACS proteins. We demonstrate that Drosophila PACS (dPACS) is required for cell division in dividing spermatocytes and neuroblasts. In primary spermatocytes, dPACS colocalizes with GOLPH3 at the Golgi stacks and is essential for maintaining Golgi architecture. In dividing cells, dPACS is necessary for central spindle stability and contractile ring constriction. dPACS and GOLPH3 proteins form a complex and are mutually dependent for localization to the cleavage site. We propose that dPACS, by associating with GOLPH3, mediates the flow of vesicle trafficking that supports furrow ingression during cytokinesis. Furthermore, loss of dPACS leads to defects in tubulin acetylation and severe bang sensitivity, a phenotype associated with seizures in flies. Together our findings suggest that a Drosophila PACS disease model may contribute to understanding the molecular mechanisms underpinning human PACS syndromes.
    Keywords:  Drosophila; PACS; cytokinesis; membrane trafficking; model organism; neurodevelopmental disease
    DOI:  https://doi.org/10.1098/rsob.240267
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