bims-micesi 2025-08-24 papers

Issue of 2025–08–24
six papers selected by
Valentina Piano, Uniklinik Köln

Nat Commun. 2025 Aug 18. 16(1): 7676

CENcyclopedia: dynamic landscape of kinetochore architecture throughout the cell cycle.

Yu-Chia Chen, Ece Kilic, Evelyn Wang, Will Rossman, Aussie Suzuki.

The kinetochore, an intricate macromolecular protein complex located on chromosomes, plays a pivotal role in orchestrating chromosome segregation. It functions as a versatile platform for microtubule assembly, diligently monitors microtubule binding fidelity, and acts as a force coupler. Comprising over 100 distinct proteins, many of which exist in multiple copies, the kinetochore's composition dynamically changes throughout the cell cycle, responding to specific timing and conditions. This dynamicity is important for establishing functional kinetochores, yet the regulatory mechanisms of these dynamics have largely remained elusive. In this study, we employed advanced quantitative immunofluorescence techniques to meticulously chart the dynamics of kinetochore protein levels across the cell cycle. These findings offer a comprehensive view of the dynamic landscape of kinetochore architecture, shedding light on the detailed mechanisms of microtubule interaction and the nuanced characteristics of kinetochore proteins. This study significantly advances our understanding of the molecular coordination underlying chromosome segregation.

DOI: https://doi.org/10.1038/s41467-025-62316-6

Cytoskeleton (Hoboken). 2025 Aug 19.

Discovery of an Atypical Arp2/3 Complex in Malaria Parasites Sheds New Light on Nuclear Actin.

Franziska Hentzschel, Friedrich Frischknecht, Matthias Marti.

The Arp2/3 complex is a key actin nucleator essential for cytoskeletal dynamics in eukaryotes. Previously believed absent in apicomplexan parasites, we recently identified an atypical Arp2/3 complex in malaria parasites consisting of five divergent subunits and a putative kinetochore-associated factor. This complex ensures proper kinetochore-spindle attachment during male gametogenesis, likely by nucleating actin at the mitotic spindle. Disruption of Arp2/3 function or actin polymerization leads to defective DNA segregation into gametes and developmental arrest of the parasite in the mosquito. Our findings reveal unexpected diversity in Arp2/3 complex composition and function, highlighting specialized adaptations in malaria parasites and expanding our understanding of the Arp2/3 complex and actin functions during mitosis. Here, we discuss some of the open questions that need to be addressed to fully understand the molecular mechanism of this unusual Arp2/3 complex and its essential role in malaria transmission.

Keywords: Plasmodium ; Arp2/3 complex; actin; mitosis

DOI: https://doi.org/10.1002/cm.70030

EMBO J. 2025 Aug 18.

NANOG is repurposed after implantation to repress Sox2 and begin pluripotency extinction.

Frederick C K Wong, Man Zhang, Ella Thomson, Linus J Schumacher, Anestis Tsakiridis, James Ashmore, Tong Li, Guillaume Blin, Eleni Karagianni, Nicholas P Mullin, Ian Chambers, Valerie Wilson.

Loss of pluripotency is an essential step in post-implantation development that facilitates the emergence of somatic cell identities essential for gastrulation. Before implantation, pluripotent cell identity is governed by a gene regulatory network that includes the key transcription factors SOX2 and NANOG. However, it is unclear how the pluripotency gene regulatory network is dissolved to enable lineage restriction. Here, we show that SOX2 is required for post-implantation pluripotent identity in the mouse, and cells that lose SOX2 expression in the posterior epiblast are no longer pluripotent. Using in vitro and in vivo analyses, we demonstrate anticorrelated expression of NANOG and SOX2 preceding gastrulation, culminating in an early disappearance of pluripotent identity from posterior NANOGhigh/SOX2low epiblast. Surprisingly, Sox2 expression is repressed by NANOG and embryos with post-implantation deletion of Nanog maintain posterior SOX2 expression. Our results demonstrate that the distinctive features of post-implantation pluripotency are underpinned by altered functionality of pluripotency transcription factors, ensuring correct spatio-temporal loss of embryonic pluripotency.

Keywords: Embryo; NANOG; Pluripotency; Post Implantation; SOX2

DOI: https://doi.org/10.1038/s44318-025-00527-9

Res Sq. 2025 Aug 13. pii: rs.3.rs-7303237. [Epub ahead of print]

Oncogenic p53 induces mitotic errors in lung cancer cells by recopying DNA replication forks conferring targetable proliferation advantage.

Swati Palit Deb, Shilpa Singh, Lilia Gheghiani, Rebecca Frum, Steven Grossman, Brad Windle, Sumitra Deb.

Oncogenic p53 mutations (Onc-p53) are frequent in lung and many other solid tumors often associated with chromosome aberrations. Why cells with Onc-p53 develop chromosomal aberrations and whether the abnormalities contribute to tumor growth remain elusive. Evidence in this communication demonstrate for the first time that replication stress induced by Onc-p53 triggers re-copying of DNA replication forks, which generates replication intermediates that cause persistent mitotic aberration and DNA segregation errors. Replication intermediates from re-copied replication forks induced by Onc-p53 activate ATM signaling, which stabilizes Onc-p53, reinforces its ability to upregulate replication factors for sustaining replication stress, thus generating a feedforward cycle accelerating tumor formation. In agreement with this observation our time lapse video microscopy show in real time that persistent mitotic aberration and DNA segregation errors induced by Onc-p53 confer selective growth advantage. Accordingly, human lung tumors with Onc-p53 show selection of cells with mitotic aberration during serial passages. Knock down of active replication forks reduces re-copied fork generation by Onc-p53 and specifically induces apoptotic death of lung cancer cells expressing Onc-p53 in xenograft lung tumors synergistically in cooperation with inhibitors of ATM activation, deselecting cells with Onc-p53 with mitotic errors. This communication reveals a novel mechanism which interconnects replication stress induced by Onc-p53 to its stabilization and ability to generate chromosomal aberration in lung cancer cells that both accelerate tumor growth and serve as a targetable therapeutic vulnerability. These findings will be extremely valuable for tumor-specific treatment of a high percentage of cancer patients with p53 mutation.

DOI: https://doi.org/10.21203/rs.3.rs-7303237/v1

Glycoconj J. 2025 Aug 18.

Cell cycle regulation in cancer cells by O-GlcNAcylation.

Ulises González-González, María Cristina Castañeda-Patlán, María Teresa Hernández-Huerta, Jesús Hernández-Juárez, Edgar Zenteno-Galindo, Carlos Josué Solórzano-Mata.

Cancer remains one of the leading causes of death worldwide. Due to the multiple molecular mechanisms involved in cell transformation, its biology continues to be studied from different perspectives and in other research areas. A hallmark of cancer is its accelerated proliferation and overactivation of the cell cycle, caused by a dysregulated metabolism and the activation of different signaling pathways, such as the PI3/K-Akt pathway. On the other hand, the hexosamine biosynthetic pathway plays an essential role in producing UDP-GlcNAc, the primary substrate for O-GlcNAcylation. This non-canonical post-translational modification regulates protein stability, localization and interactions. This work aims to examine the role of the O-GlcNAcylation in regulating the cell cycle across diverse types of cancer and its involvement in the PI3/K-Akt pathway as a promoter of the cell cycle progression. Additionally, the study also proposes new alternatives for cancer diagnosis, prognosis, and treatment.

Keywords: O-GlcNAcylation; Cancer; Cell cycle; Regulation

DOI: https://doi.org/10.1007/s10719-025-10189-8

Med Int (Lond). 2025 Sep-Oct;5(5):5(5): 59

Downregulation of kinetochore-associated 1 gene increases lagging chromosomes and contributes to chromosomal instability in gastric cancer cells.

Daiki Ohsaki, Kazuki Kanayama.

Gastric cancer (GC) is classified into four molecular subtypes according to the Epstein-Barr virus-positive status, microsatellite instability, genomic stability and chromosomal instability (CIN). The CIN subtype is characterized by a high frequency of gene amplifications in receptor tyrosine kinases (RTKs) and a poor prognosis. In addition, the CIN subtype often exhibits intratumoral heterogeneity and indicates insensitivity to targeted drugs. Elucidating the molecular mechanisms of CIN in GC is therapeutically crucial; however, the molecular mechanisms involved are not yet fully understood. The kinetochore-associated 1 (KNTC1) gene encodes kinetochore-associated protein 1 (KNTC1), a major component of the outer kinetochore. The downregulation of KNTC1 causes a high frequency of lagging chromosomes and consequent aneuploidy and CIN in Drosophila and Caenorhabditis elegans. However, the association between KNTC1 and CIN in GC has not yet been clarified. Therefore, the present study investigated the role of KNTC1 in GC CIN. It was found that GC cell lines with a high frequency of lagging chromosomes had a low KNTC1 mRNA expression. Notably, KNTC1 knockdown increased the frequency of lagging chromosomes in GC cell lines. In particular, GC cell lines with the amplification of RTK genes exhibited a significant increase in the frequency of lagging chromosomes. On the whole, the findings of the present study suggest that the suppression of KNTC1 expression may contribute to CIN in GC and may be involved in the generation of intratumoral genetic heterogeneity in GC.

Keywords: chromosomal instability; gastric cancer; kinetochore-associated 1 gene; lagging chromosome; receptor tyrosine kinase

DOI: https://doi.org/10.3892/mi.2025.258