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At least 19 recordsLinked to original sources
PubMed2026

Cohesin preservation across mitosis contributes to restart transcription via Cdk9-mediated activation of RNAPol2.

Cohesin organizes 3D genome architecture yet its acute depletion in vitro minimally affects transcription, leaving its regulatory role puzzling. We hypothesized that cohesin function is relevant when first encounters chromatin after mitosis. Using in vivo labeling and cell-cycle synchronization in human cells, we demonstrate that cohesin complexes persist through mitosis. This inherited pool dominates over newly translated cohesin during telophase-G1, highlighting the relevance of such transmission. Acute depletion of cohesin Rad21 at mitotic exit impairs the expression of hundreds of genes, mostly downregulated, enriched on functions related to tissue growth and development. Rad21 binds the promoter of this group of genes. Remarkably, we uncover a direct interaction during the M-G1 transition between Rad21 and Cdk9, the kinase component of transcription elongation factor b (pTEFb) complex. Rad21 loss impairs Cdk9 chromatin association, reducing active-elongating RNAPol2 at down-regulated genes. Overall, preserving cohesin across mitosis enables post-mitotic transcriptional reactivation via Cdk9, establishing tissue-specific expression programs.

RNA polymerase 2↗
PubMed2026

The periphery of nuclear speckles defines a spatially and temporally regulated compartment of long-lived intron-retained RNAs that resolves during mitosis.

RNA localization adds a fundamental layer to gene expression by determining when and where translation-ready mRNAs become available, yet how this timing is coordinated with nuclear architecture and cell-cycle progression remains unclear. Here we identify a subnuclear RNA niche at the nuclear speckle periphery that couples intron retention to cell-cycle-timed RNA release. Using compartment-resolved transcriptional inhibition, sequence-based deep learning and single-molecule and super-resolution RNA imaging in human pluripotent stem cells, we define a class of nuclear RNAs with long-lived retained introns that persist for hours and are enriched in transcripts encoding regulators of genome maintenance and mitosis, including centromere and kinetochore assembly, DNA repair and telomere maintenance. Long-lived retained introns exhibit elevated GC content, predicted structural stability and enrichment for nuclear speckle-associated RNA-binding proteins. In interphase, these RNAs localize to a distinct nuclear speckle-peripheral RNA niche in a spatial arrangement conserved across cell types. During mitotic remodelling, they undergo coordinated, kinase-dependent splicing and are released into the cytoplasm of early G1 daughter cells. Together, these findings link cis-encoded intronic features, subnuclear organization and mitotic remodelling to temporal control of RNA fate.

Mitosis↗
PubMed2025

The Dynamics of the ESCRT Machinery in Open Mitosis from Physiology to Pathology.

The Endosomal Sorting Complex Required for Transport (ESCRT) is a highly conserved machinery best known for its role in endosomal trafficking and membrane remodeling. Increasing evidence shows that ESCRT components are also key regulators during open mitosis, where precise membrane dynamics are essential for nuclear envelope reformation and spindle disassembly. In this review, we explore how the ESCRT machinery coordinates mitotic processes under physiological conditions and how their dysregulation contributes to genomic instability, altered cell division, and disease. We highlight recent findings on the spatiotemporal control of ESCRT recruitment at mitotic membranes, the interplay with chromatin and nuclear envelope-associated factors, and the consequences of defective ESCRT function in pathological contexts such as cancer and neurodegeneration. By connecting molecular mechanisms with cellular outcomes, we provide an integrated view of how the ESCRT machinery acts as critical guardian of mitotic fidelity and offer some routes for the identification of potential therapeutic targets in human disease.

Humans↗
PubMed2025

Plasmodium ARK1 regulates spindle formation during atypical mitosis and forms a divergent chromosomal passenger complex.

Mitosis in Plasmodium spp., the causative agent of malaria, is fundamentally different from model eukaryotes, proceeding via a bipartite microtubule organising centre (MTOC) and lacking canonical regulators such as Polo and Bub1 kinases. During schizogony, asynchronous nuclear replication produces a multinucleate schizont, while rapid male gametogony generates an octaploid nucleus before gamete formation. Here, we identify Aurora-related kinase 1 (ARK1) as a key component of inner MTOC and spindle formation, controlling kinetochore dynamics and driving mitotic progression. Conditional ARK1 depletion disrupts spindle biogenesis, kinetochore segregation, karyokinesis and cytokinesis in both stages, and affects parasite transmission. Interactome analysis reveals ARK1 as the catalytic core of a non-canonical chromosomal passenger complex (CPC) containing two divergent inner centromere proteins (INCENPs) but lacking Survivin and Borealin. Comparative genomics indicates this CPC architecture arose early in Apicomplexa, replacing canonical centromere-targeting modules. These findings uncover a distinct mitotic machinery in Plasmodium and identify the ARK1-INCENP interface as a potential multistage target for malaria therapeutic intervention.

Aurora kinase↗
PubMed2025

The Role of Polo-Like Kinase 1 (PLK1) O-GlcNAcylation in Mitosis.

Polo-like kinase 1 (PLK1) is a crucial mitotic kinase that is implicated in various aspects of cell cycle. Many post-translational modifications have been identified on PLK1 to regulate its activation, stability, and localization. PLK1 has been shown previously to colocalize with the O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT), and OGT regulates PLK1 stability. In our recent work, we show that PLK1 is O-GlcNAcylated by click chemistry. Using stepped collisional energy/higher energy collision dissociation mass spectrometry, we mapped the PLK1 O-GlcNAc site to be T291. We further utilized fluorescent activated cell sorting and time-lapse microscopy to assess the mitotic defects of PLK1 O-GlcNAc mutants. In vivo studies in mouse xenograft demonstrated that it promoted uterine cancer tumorigenesis. In this chapter, we delineate the methodologies we used in studying PLK1 O-GlcNAcylation, including click chemistry, stepped collisional energy/higher energy collision dissociation mass spectrometry, fluorescent activated cell sorting, time-lapse microscopy, and mouse xenograft assays.

Polo-Like Kinase 1↗
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↗
PubMed2025

Studying Mitotic Phosphorylation in Drosophila.

Mitosis is largely controlled by the reversible phosphorylation of effector proteins. The addition or removal of phosphate groups alters the activities of these proteins, resulting in changes in chromosome structure, cytoskeletal dynamics, nuclear envelope integrity, and other transformations that must occur as a cell progresses through mitosis. Drosophila has been instrumental in the elucidation of the molecular mechanisms of mitosis, which are mostly conserved among animals. In this model system, sophisticated genetic tools can be used to study mitosis in different tissues during development in vivo. Drosophila cell culture affords complementary possibilities. In this chapter, we present a phosphoproteomic protocol using Drosophila cell culture to identify phosphorylation sites that depend on mitotic kinases and phosphatases. We also provide protocols to dissect the roles of the identified sites in the regulation of protein interactions and localization during mitosis, using Drosophila embryos. We emphasize the advantages of the selected methods compared to possible alternatives in Drosophila or in other systems.

Animals↗
PubMed2026

Live dynamics of induced cell-cell fusion between mitotic and interphasic cells.

The cell cycle is tightly regulated by checkpoint mechanisms that ensure faithful duplication and segregation of the genome. Here, we induced cell-cell fusion between mitotic and interphase cells to study how nuclei from different cell cycle stages behave in a shared cytoplasm. We found that mitosis is a dominant cell cycle state: the mitotic cytoplasm can drive interphase nuclei into mitosis, whereas, in high ratios of interphase versus mitotic nuclei, fusion forced mitotic nuclei to exit mitosis. Both outcomes represent checkpoint override events with impactful consequences. Interphase nuclei forced into mitosis form aberrant mitotic spindles, show partially condensed DNA and ultimately undergo mitotic catastrophe. Conversely, forced mitotic exit resulted in reformation of nuclear envelope membranes around condensed chromosomes, forming nuclei with a defective nuclear import machinery. Altogether, cell-cell fusion revealed the consequences of checkpoint override, forcing nuclei through untimely cell cycle transitions, and highlight how cell-cell fusion experiments can be a powerful system to study how competing cytoplasmic states are integrated in a shared cytoplasm, such as in muscle, placenta formation and in cancer.

Cell cycle↗
PubMed2025

Targeting Mitotic Exit in Malignant Cells.

In order to sustain genomic stability by correct DNA replication and mitosis and thus avoid malignant transformation of cells, the cell cycle is a strictly regulated process. Aberrant cell cycle regulation and defects in mitosis in malignant cells are targets of various cancer therapies. Cancer cells may survive antimitotic treatment due to mitotic slippage with a residual activity of the ubiquitin ligase anaphase-promoting complex (APC/C) and a continuous slow ubiquitin-proteasome-dependent cyclin B-degradation leading to mitotic exit. The combination of antimitotic chemotherapeutics with proteasome inhibitors to block cyclin B-proteolysis or with targeted inhibitors of the APC/C and the antiapoptotic protein Mcl-1 seems a promising approach to improve treatment response in different malignancies by enhancing mitotic arrest and apoptosis.The influence of conventional spindle poisons and new targeted substances and of their combinations on mitosis and apoptosis has not yet been conclusively clarified. Most models have been verified on cell lines whose biology may differ from that of tumors growing in vivo. To study the impact of various antimitotic substances on cell proliferation, especially detect onset of apoptosis depending on different cell cycle phases and thus to identify a possibly entity-dependent mechanism of those agents and their combinations, a combined approach with live-cell imaging and soft-agar colony assays in cultured patient-derived xenografts (PDX) was established.

Humans↗
PubMed2025

HDAC6-dependent deacetylation of SAE2 enhances SUMO1 conjugation for mitotic integrity.

Mammalian cells express three conjugatable SUMO variants: SUMO1 and the closely related SUMO2 and SUMO3 (together referred to as SUMO2/3). While some substrates are modified by both, others show a clear preference, though the basis for this selectivity remains unclear. Here, we examine a modification of the catalytic component of the human SUMO activation enzyme, SAE2. We find that lysine 164 of SAE2 undergoes HDAC6-dependent deacetylation during mitosis. A non-deacetylatable acetyl-mimetic mutant, SAE2-K164Q, selectively enhances SUMO2 over SUMO1 activation and conjugation, and distinguishes between SUMO1 and SUMO2/3 based on differences in their C-terminal tails. Complementation of SAE2-deficient or inhibited cells with SAE2-K164Q suppresses mitotic SUMO1 conjugation and promotes multipolar spindle formation. We identify NuMA as a SUMO E1-dependent substrate and demonstrate that mitotic defects caused by SAE2-K164Q or HDAC6 inhibition are rescued by SUMO1 overexpression or expression of a GFP-SUMO1-NuMA-K1766R fusion. These results support a model in which SAE1:SAE2 deacetylation during early mitosis promotes SUMO1 conjugation to ensure mitotic fidelity, highlighting a regulatory role for the SUMO-activating enzyme in the selection of SUMO proteins.

Humans↗
PubMed2026

Dynamic chromatin tethering of MDC1 regulates genome stability.

DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions because they disrupt the connectivity of the DNA strand. Homologous recombination (HR) is a high-fidelity DSB repair pathway that copies the sequence spanning the break from a homologous template, but how DNA ends are held together during HR remains unclear. Here we demonstrate that the proline-serine-threonine (PST) repeat region of Mediator of DNA Damage Checkpoint 1 (MDC1) is a multivalent nucleosome-binding domain, sufficient to tether chromatin in multiple contexts. In interphase, the constitutive chromatin association of MDC1 is critical for RAD51 loading and efficient HR. In mitosis, PST-mediated chromatin binding is attenuated by phosphorylation, preventing aberrant chromosomal interactions while preserving DNA tethering by the MDC1-TOPBP1-CIP2A complex. In total, this work demonstrates that the PST repeat region of MDC1 is a multivalent nucleosome-binding domain with tunable affinity that supports DSB repair by HR and maintains genome stability during mitosis.

Genomic Instability↗
PubMed2026

Targeting KIFC1 to disrupt centrosome clustering and trigger anaphase catastrophe in small-cell lung cancer.

Supernumerary centrosomes are a hallmark of cancer. To maintain viability, cancer cells cluster these centrosomes during mitosis, enabling bipolar division similar to that of normal cells. Disruption of this centrosome clustering leads to multipolar anaphase and apoptosis (anaphase catastrophe), which selectively eliminates cancer cells harboring supernumerary centrosomes. In this context, because the motor protein KIFC1 contributes to centrosome clustering, we investigated whether targeting of this mechanism through KIFC1 inhibition could be exploited in small-cell lung cancer (SCLC), an aggressive malignancy with limited treatment options and poor prognosis. Through in silico and in vitro analyses, as well as IHC of clinical samples, we found that KIFC1 is overexpressed and that centrosome amplification occurs more frequently in SCLC compared with normal tissues and other cancer types. Pharmacological and genetic inhibition of KIFC1 disrupted the clustering of supernumerary centrosomes, triggered multipolar mitosis, and exerted antineoplastic effects in SCLC cells, with minimal effects on noncancerous cells. These findings were validated and extended in vivo using SCLC xenograft models. Finally, cotargeting KIFC1 and the centrosome duplication regulator PLK4 further enhanced growth suppression in SCLC cells. Together, these results suggest that disrupting centrosome clustering and triggering anaphase catastrophe via KIFC1 inhibition may represent a promising therapeutic strategy for SCLC.

Humans↗
PubMed2026

Spindle Assembly Checkpoint Competency Determines Sensitivity to KIF18A Inhibition in Small-Cell Lung Cancer.

BACKGROUND: Small-cell lung cancer (SCLC) is characterized by pervasive chromosomal instability (CIN) and remains largely refractory to targeted therapies. KIF18A, a motor protein that regulates chromosome alignment during mitosis, has emerged as a selective dependency in CIN-high tumors. Whether this dependency extends to SCLC, a prototypical CIN-high cancer, has not been established, and biomarkers predicting response to KIF18A inhibition, currently in clinical trials, are lacking. METHODS: We integrated analyses of patient tumor datasets, neuroendocrine (NE) and non- NE SCLC cell lines, and functional perturbation models to define the determinants of response to KIF18A inhibition. Chromosomal instability metrics, transcriptional programs, mitotic dynamics, and spindle assembly checkpoint (SAC) function were assessed using genomic profiling, live-cell imaging, genetic perturbation, and pharmacologic inhibition. RESULTS: KIF18A expression was elevated in SCLC tumors and correlated with CIN-associated transcriptional programs, proliferative markers, and NE status; however, these features did not predict sensitivity to KIF18A inhibition. Instead, response was determined by the functional integrity of the SAC. SAC-proficient SCLC cells underwent sustained mitotic arrest followed by apoptotic cell death upon KIF18A inhibition, whereas SAC-defective cells failed to maintain checkpoint activation and survived. Mechanistically, resistant cells exhibited impaired kinetochore recruitment of core SAC components, including MAD1 and BUBR1. Importantly, transient induction of acute CIN through MPS1 inhibition partially restored sensitivity to KIF18A inhibition in resistant models. CONCLUSIONS: This study provides the first mechanistic characterization of KIF18A dependency in SCLC, identifying SAC competency as the primary determinant of response. These findings establish a biologically informed framework for patient stratification and rational combination strategies. TRANSLATIONAL RELEVANCE: Small-cell lung cancer (SCLC) is an aggressive malignancy with few effective targeted therapies and marked chromosomal instability. KIF18A has emerged as a potential therapeutic target in genomically unstable cancers, but biomarkers predicting response to KIF18A inhibition are lacking. We demonstrate that sensitivity to KIF18A inhibition in SCLC is determined not by KIF18A expression, neuroendocrine subtype, or baseline chromosomal instability, but by the functional integrity of the spindle assembly checkpoint (SAC). SCLC cells with intact SAC signaling undergo sustained mitotic arrest and apoptosis upon KIF18A inhibition, whereas SAC-defective cells bypass checkpoint activation and survive aberrant mitosis. Notably, transient induction of acute chromosomal instability through MPS1 inhibition partially restores sensitivity in resistant models. Together, these findings identify mitotic checkpoint competency as a mechanistic determinant and candidate predictive biomarker for KIF18A-targeted therapies, providing a biologically informed framework for patient stratification and rational combination strategies relevant to ongoing KIF18A inhibitor clinical trials.

Journal Article↗
PubMed2025

Synaptic vesicle glycoprotein 2 enables viable aneuploidy following centrosome amplification.

Amplified centrosome number causes genomic instability, most severely through division into >2 aneuploid daughter cells (multipolar mitosis). Several mechanisms that suppress multipolar division have been uncovered, yet mechanisms that favor viable multipolar division are poorly understood. To uncover factors that promote viability in cells with frequent centrosome amplification and multipolar division, we conducted an unbiased Drosophila genetic screen. In 642 mutagenized lines, we exploited the ability of intestinal papillar cells to form and function despite multipolar divisions. Our top hit is an unnamed gene, CG3168. We name this gene synaptic vesicle glycoprotein 2, reflecting homology to human Synaptic Vesicle Glycoprotein 2 (SV2) proteins. GFP-tagged SV2 localizes to the plasma membrane. In cells with amplified centrosomes, SV2 positions membrane-adjacent centrosomes, which prevents severe errors in chromosome alignment and segregation. Our results uncover membrane-based multipolar division regulation and reveal a novel vulnerability in cells with common cancer properties.

Centrosome↗
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↗
PubMed2025

Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation.

Across metazoan species, the centromere-specific histone variant CENP-A is essential for accurate chromosome segregation, yet its regulation during the mammalian parental-to-zygote transition is poorly understood. To address this, we generated a CENP-A-mScarlet mouse model that revealed sex-specific dynamics: mature sperm retain 10% of the CENP-A levels present in MII oocytes. However, this difference is resolved in zygotes prior to the first mitosis, using maternally inherited cytoplasmic CENP-A. Notably, the increase in CENP-A at paternal centromeres is independent of sensing CENP-A asymmetry or the presence of maternal chromosomes. Instead, CENP-A equalization relies on the asymmetric recruitment of maternal CENP-C to paternal centromeres. Depletion of maternal CENP-A decreases total CENP-A in both pronuclei without disrupting equalization. In contrast, reducing maternal CENP-C or disruption of its dimerization function impairs CENP-A equalization and chromosome segregation. Therefore, maternal CENP-C acts as a key epigenetic regulator that resets centromeric symmetry at fertilization to preserve genome integrity.

Animals↗
PubMed2026

Mitotic microhomology-mediated break-induced replication promotes chromoanasynthesis.

Chromoanasynthesis is a form of complex chromosomal rearrangement (CCR) commonly detected in cancers and congenital disorders, but the mechanism underlying its generation remain elusive. Here we develop a single-molecule long-read DNA sequencing approach to characterise ultra-complex mutational events, consistent with chromoanasynthesis, occurring at shortened telomeres and sub-telomeric DNA double-strand breaks in human cells. Our data reveal that chromoanasynthesis is generated by microhomology-mediated break-induced replication (MM-BIR), occurring specifically in mitosis. Surprisingly, this mitotic pathway involves a collaboration between microhomology-mediated end-joining (MMEJ) and BIR, where MMEJ proteins initiate a Polδ-dependent BIR pathway that is regulated by PIF1, POLD3 and PCNA. This pathway is highly prone to template switching and can generate dramatic amplification of genomic loci in a single event. Our findings help explain the extreme mutagenic nature of chromoanasynthesis and establish mitotic MM-BIR as a key driver of CCRs, with important implications for the origin of cancers and congenital disorders.

Humans↗
PubMed2026

Plasticity of extrachromosomal DNA segregation during drug adaptation.

Uneven segregation during mitosis is a striking feature of extrachromosomal DNA (ecDNA). Because ecDNA lacks a centromere, it is thought to segregate stochastically, generating intratumoral heterogeneity in genomic copy number. Drug treatment can readily change ecDNA copy number, enabling cells to acquire drug resistance, yet whether these changes reflect static selection of pre-existing clones or active reconfiguration under stress remains unresolved. To address this, we develop a high-throughput framework combining single-cell DNA sequencing with cellular barcoding for clonal tracking. Single-cell cloning reveals that not all clones exhibit identical segregation modes even under drug-free conditions. Under treatment, resistant populations do not simply arise from pre-existing clones with favorable ecDNA states; instead, some clones actively reconfigure their segregation behavior to generate resistant cells. Thus, although ecDNA generally segregates stochastically, it can undergo nonrandom, actively regulated segregation under drug stress, raising the possibility of therapeutically targeting ecDNA segregation mechanisms to counteract adaptive resistance.

Extrachromosomal DNA↗