bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2024–10–13
eleven papers selected by
Valentina Piano, Uniklinik Köln
  1. An atlas of RNA-dependent proteins in cell division reveals the riboregulation of mitotic protein-protein interactions.
  2. Haploidy-linked cell proliferation defects limit larval growth in zebrafish.
  3. HNF1β bookmarking involves Topoisomerase 1 activation and DNA topology relaxation in mitotic chromatin.
  4. Genetic interaction mapping of Aurora protein kinases in mouse oocytes.
  5. Mitotic spindle positioning protein serves as prognostic biomarker in patients with colorectal cancer.
  6. MAD1 upregulation sensitizes to inflammation-mediated tumor formation.
  7. YAP Overcomes Mechanical Barriers to Induce Mitotic Rounding and Adult Cardiomyocyte Division.
  8. Discovery of new pyrazole-4-carboxamide analogues as potential anticancer agents targeting dual aurora kinase A and B.
  9. The formation and propagation of human Robertsonian chromosomes.
  10. Probing the Nanonewton Mitotic Cell Deformation Force by Ion-Resonance-Enhanced Photonics Force Microscopy.
  11. Cellular and molecular mechanisms of asymmetric stem cell division in tissue homeostasis.
  1. bioRxiv. 2024 Sep 26. pii: 2024.09.25.614981. [Epub ahead of print]
    An atlas of RNA-dependent proteins in cell division reveals the riboregulation of mitotic protein-protein interactions.
    Varshni Rajagopal, Jeanette Seiler, Isha Nasa, Simona Cantarella, Jana Theiss, Franziska Herget, Bianca Kaifer, Martin Schneider, Dominic Helm, Julian König, Kathi Zarnack, Sven Diederichs, Arminja N Kettenbach, Maïwen Caudron-Herger.
      Ribonucleoprotein complexes are dynamic assemblies of RNA with RNA-binding proteins (RBPs), which can modulate the fate of the RNA molecules from transcription to degradation. Vice versa, RNA can regulate the interactions and functions of the associated proteins. Dysregulation of RBPs is linked to diseases such as cancer and neurological disorders. RNA and RBPs are present in mitotic structures like the centrosomes and spindle microtubules, but their influence on mitotic spindle integrity remains unknown. Thus, we applied the R-DeeP strategy for the proteome-wide identification of RNA-dependent proteins and complexes to cells synchronized in mitosis versus interphase. The resulting atlas of RNA-dependent proteins in cell division can be accessed through the R-DeeP 3.0 database (R-DeeP3.dkfz.de). It revealed key mitotic factors as RNA-dependent such as AURKA, KIFC1 and TPX2 that were linked to RNA despite their lack of canonical RNA-binding domains. KIFC1 was identified as a new interaction partner and phosphorylation substrate of AURKA at S 349 and T 359 . In addition, KIFC1 interacted with both, AURKA and TPX2, in an RNA-dependent manner. Our data suggest a riboregulation of mitotic protein-protein interactions during spindle assembly, offering new perspectives on the control of cell division processes by RNA-protein complexes.
    Highlights: Differential R-DeeP screens in mitosis and interphase are provided as a resource in a user-friendly database at R-DeeP3.dkfz.deAn atlas of RNA-dependent proteins in cell division identifies a substantial number of unconventional RNA-binding proteins among mitotic factorsInvestigation of protein-protein interactions reveals KIFC1 as a new AURKA and TPX2 interaction partner during spindle assemblyKIFC1, AURKA and TPX2 interact with each other in an RNA-dependent manner and directly bind to RNA AURKA phosphorylates KIFC1 at residues S 349 and T 359.
    DOI:  https://doi.org/10.1101/2024.09.25.614981
  2. Open Biol. 2024 Oct;14(10): 240126
    Haploidy-linked cell proliferation defects limit larval growth in zebrafish.
    Kan Yaguchi, Daiki Saito, Triveni Menon, Akira Matsura, Miyu Hosono, Takeomi Mizutani, Tomoya Kotani, Sreelaja Nair, Ryota Uehara.
      Haploid larvae in non-mammalian vertebrates are lethal, with characteristic organ growth retardation collectively called 'haploid syndrome'. In contrast to mammals, whose haploid intolerance is attributed to imprinting misregulation, the cellular principle of haploidy-linked defects in non-mammalian vertebrates remains unknown. Here, we investigated cellular defects that disrupt the ontogeny of gynogenetic haploid zebrafish larvae. Unlike diploid control larvae, haploid larvae manifested unscheduled cell death at the organogenesis stage, attributed to haploidy-linked p53 upregulation. Moreover, we found that haploid larvae specifically suffered the gradual aggravation of mitotic spindle monopolarization during 1-3 days post-fertilization, causing spindle assembly checkpoint-mediated mitotic arrest throughout the entire body. High-resolution imaging revealed that this mitotic defect accompanied the haploidy-linked centrosome loss occurring concomitantly with the gradual decrease in larval cell size. Either resolution of mitotic arrest or depletion of p53 partially improved organ growth in haploid larvae. Based on these results, we propose that haploidy-linked mitotic defects and cell death are parts of critical cellular causes shared among vertebrates that limit the larval growth in the haploid state, contributing to an evolutionary constraint on allowable ploidy status in the vertebrate life cycle.
    Keywords:  centrosome; ploidy; zebrafish
    DOI:  https://doi.org/10.1098/rsob.240126
  3. Cell Rep. 2024 Oct 08. pii: S2211-1247(24)01156-2. [Epub ahead of print]43(10): 114805
    HNF1β bookmarking involves Topoisomerase 1 activation and DNA topology relaxation in mitotic chromatin.
    Alessia Bagattin, Salvina Laura Tammaccaro, Magali Chiral, Munevver Parla Makinistoglu, Nicolas Zimmermann, Jonathan Lerner, Serge Garbay, Nicolas Kuperwasser, Marco Pontoglio.
      HNF1β (HNF1B) is a transcription factor frequently mutated in patients with developmental renal disease. It binds to mitotic chromatin and reactivates gene expression after mitosis, a phenomenon referred to as bookmarking. Using a crosslinking method that circumvents the artifacts of formaldehyde, we demonstrate that HNF1β remains associated with chromatin in a sequence-specific way in both interphase and mitosis. We identify an HNF1β-interacting protein, BTBD2, that enables the interaction and activation of Topoisomerase 1 (TOP1) exclusively during mitosis. Our study identifies a shared microhomology domain between HNF1β and TOP1, where a mutation, found in "maturity onset diabetes of the young" patients, disrupts their interaction. Importantly, HNF1β recruits TOP1 and induces DNA relaxation around HNF1β mitotic chromatin sites, elucidating its crucial role in chromatin remodeling and gene reactivation after mitotic exit. These findings shed light on how HNF1β reactivates target gene expression after mitosis, providing insights into its crucial role in maintenance of cellular identity.
    Keywords:  BTBD2; CP: Genomics; CP: Molecular biology; ChIP-seq; DNA topology; HNF1B; TOP1; epigenetics; mitotic bookmarking; renal disease; transcription
    DOI:  https://doi.org/10.1016/j.celrep.2024.114805
  4. Front Cell Dev Biol. 2024 ;12 1455280
    Genetic interaction mapping of Aurora protein kinases in mouse oocytes.
    Cecilia S Blengini, Karen Schindler.
      The Aurora Kinases (AURKs) are a family of serine-threonine protein kinases critical for cell division. Somatic cells express only AURKA and AURKB. However, mammalian germ cells and some cancer cells express all three isoforms. A major question in the field has been determining the molecular and cellular changes when cells express three instead of two aurora kinases. Using a systematic genetic approach involving different Aurora kinase oocyte-specific knockout combinations, we completed an oocyte-AURK genetic interaction map and show that one genomic copy of Aurka is necessary and sufficient to support female fertility and oocyte meiosis. We further confirm that AURKB and AURKC alone cannot compensate for AURKA. These results highlight the importance of AURKA in mouse oocytes, demonstrating that it is required for spindle formation and proper chromosome segregation. Surprisingly, a percentage of oocytes that lack AURKB can complete meiosis I, but the quality of those eggs is compromised, suggesting a role in AURKB to regulate spindle assembly checkpoint or control the cell cycle. Together with our previous studies, we wholly define the genetic interplay among the Aurora kinases and reinforce the importance of AURKA expression in oocyte meiosis.
    Keywords:  aneuploidy; aurora kinase; meiosis; mouse model; oocyte
    DOI:  https://doi.org/10.3389/fcell.2024.1455280
  5. Scand J Gastroenterol. 2024 Oct 05. 1-9
    Mitotic spindle positioning protein serves as prognostic biomarker in patients with colorectal cancer.
    Jin Li, Aimin Zhang, Weilun Li, Zeye Duan, Suqin Li, Yunyan Fan, Haiyan Hao.
       BACKGROUND: Colorectal cancer (CRC) ranks among the most aggressive types of cancer globally. Currently, clinical tumor prognostic biomarkers still lack accuracy. Mitotic spindle positioning (MISP) protein connects microtubules to the actin cytoskeleton and adhesive plaques, playing a critical role in spindle positioning, orientation, and the process of cell division. MISP can regulate the malignant biological functions of pancreatic cancer and intrahepatic cholangiocarcinoma and it acts as biomarker for prognosis, but its role in CRC remains unclear.
    METHODS: This study has collected 37 CRC tissue samples and 37 corresponding adjacent nontumor tissue samples, and 57 additional CRC tissues samples. Clinical data were obtained from the patients with CRC. MISP mRNA and protein expression levels were analyzed in normal control and CRC tissues using the GEPIA and Human Protein Atlas website. MISP protein levels in the collected tissues were analyzed using immunohistochemistry.
    RESULTS: MISP mRNA and protein expression levels were significantly increased in CRC tissues compared to adjacent nontumor tissues. Higher MISP protein levels were associated with distant metastasis, recurrence, and lower survival rates. Kaplan-Meier analysis showed that high expression levels of MISP protein were associated with recurrence and death in CRC patients. In addition, a high expression level of MISP protein, lymph node metastasis, and distance metastasis were risk factors for recurrence and a poor prognosis in patients with CRC.
    CONCLUSION: Elevated MISP protein correlated with tumor metastasis, recurrence, and lower survival rates in patients with CRC, and thus, MISP has the potential to become a prognostic marker for CRC.
    Keywords:  Colorectal cancer; gnose; metastasis; mitotic spindle positioning; pro; sur; vival
    DOI:  https://doi.org/10.1080/00365521.2024.2411405
  6. PLoS Genet. 2024 Oct 07. 20(10): e1011437
    MAD1 upregulation sensitizes to inflammation-mediated tumor formation.
    Sarah E Copeland, Santina M Snow, Jun Wan, Kristina A Matkowskyj, Richard B Halberg, Beth A Weaver.
      Mitotic Arrest Deficient 1 (gene name MAD1L1), an essential component of the mitotic spindle assembly checkpoint, is frequently overexpressed in colon cancer, which correlates with poor disease-free survival. MAD1 upregulation induces two phenotypes associated with tumor promotion in tissue culture cells-low rates of chromosomal instability (CIN) and destabilization of the tumor suppressor p53. Using CRISPR/Cas9 gene editing, we generated a novel mouse model by inserting a doxycycline (dox)-inducible promoter and HA tag into the endogenous mouse Mad1l1 gene, enabling inducible expression of HA-MAD1 following exposure to dox in the presence of the reverse tet transactivator (rtTA). A modest 2-fold overexpression of MAD1 in murine colon resulted in decreased p53 expression and increased mitotic defects consistent with CIN. After exposure to the colon-specific inflammatory agent dextran sulfate sodium (DSS), 31% of mice developed colon lesions, including a mucinous adenocarcinoma, while none formed in control animals. Lesion incidence was particularly high in male mice, 57% of which developed at least one hyperplastic polyp, adenoma or adenocarcinoma in the colon. Notably, mice expressing HA-MAD1 also developed lesions in tissues in which DSS is not expected to induce inflammation. These findings demonstrate that MAD1 upregulation is sufficient to promote colon tumorigenesis in the context of inflammation in immune-competent mice.
    DOI:  https://doi.org/10.1371/journal.pgen.1011437
  7. Circulation. 2024 Oct 11.
    YAP Overcomes Mechanical Barriers to Induce Mitotic Rounding and Adult Cardiomyocyte Division.
    Yuka Morikawa, Jong H Kim, Rich Gang Li, Lin Liu, Shijie Liu, Vaibhav Deshmukh, Matthew C Hill, James F Martin.
       BACKGROUND: Many specialized cells in adult organs acquire a state of cell cycle arrest and quiescence through unknown mechanisms. Our limited understanding of mammalian cell cycle arrest is derived primarily from cell culture models. Adult mammalian cardiomyocytes, a classic example of cell cycle arrested cells, exit the cell cycle postnatally and remain in an arrested state for the life of the organism. Cardiomyocytes can be induced to re-enter the cell cycle by YAP5SA, an active form of the Hippo signaling pathway effector YAP.
    METHODS: We performed clonal analyses to determine the cell kinetics of YAP5SA cardiomyocytes. We also performed single-cell RNA sequencing, marker gene analysis, and functional studies to examine how YAP5SA cardiomyocytes progress through the cell cycle.
    RESULTS: We discovered that YAP5SA-expressing cardiomyocytes divided efficiently, with >20% of YAP5SA cardiomyocyte clones containing ≥2 cardiomyocytes. YAP5SA cardiomyocytes re-entered cell cycle at the G1/S transition and had an S phase lasting ≈48 hours. Sarcomere disassembly is required for cardiomyocyte progression from S to G2 phase and the induction of mitotic rounding. Although oscillatory Cdk expression was induced in YAP5SA cardiomyocytes, these cells inefficiently progressed through G2 phase. This is improved by inhibiting P21 function, implicating checkpoint activity as an additional barrier to YAP5SA-induced cardiomyocyte division.
    CONCLUSIONS: Our data reveal that YAP5SA overcomes the mechanically constrained myocardial microenvironment to induce mitotic rounding with cardiomyocyte division, thus providing new insights into the in vivo mechanisms that maintain cell cycle quiescence in adult mammals.
    Keywords:  Hippo pathway; P21; YAP; cell cycle; mitotic rounding; myocyte proliferation; sarcomere disassembly
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.066004
  8. Eur J Med Chem. 2024 Oct 04. pii: S0223-5234(24)00798-0. [Epub ahead of print]280 116917
    Discovery of new pyrazole-4-carboxamide analogues as potential anticancer agents targeting dual aurora kinase A and B.
    Digambar Yevale, Nishith Teraiya, Twinkle Lalwani, Mayur Dalasaniya, Saumya K Patel, Nandan Dixit, Chetan B Sangani, Sujeet Kumar, N V L Sirisha Mulukuri, Tao Huang, Yong-Tao Duan, Jie Zhang.
      Aurora kinases A and B are critical regulators of cell division and cytokinesis. Abnormal expression of Aurora kinases A and B causes chromosomal instability and disrupts several tumor suppressor and oncoprotein-controlled pathways. As a result, there has been a spike in interest in developing inhibitors against these kinases as anticancer treatments. This paper addresses the discovery, anticancer evaluation and druggability study of new pyrazole-4-carboxamide analogues as kinases inhibitors. Among the compounds, 6k demonstrated the highest cytotoxicity against HeLa and HepG2 cells, with IC50 of 0.43 μM and 0.67 μM, respectively. It selectively inhibited Aurora kinases A and B, with IC50 values of 16.3 nM and 20.2 nM, respectively, in comparison to other kinases. Molecular investigations revealed that 6k induced the inhibition of phosphorylated Thr288 (Aurora kinase A) and phosphorylated Histone H3 (Aurora kinase B), confirming its mechanism of action. Beside, compound 6k arrested the cell cycle at the G2/M phase by modulating cyclinB1 and cdc2 protein levels and increasing the Sub-G1 cell population. It also significantly increased polyploidization (>8 N) and abnormal mitosis, likely due to Aurora kinase inhibition. Furthermore, 6k boosted apoptosis through the intrinsic route, with elevated levels of p53, Bak, Bax, cleaved caspase-3, and cleaved PARP. Moreover, docking and MD simulations validated kinase inhibition-induced anticancer effects. Additionally, 6k satisfied drug-likeness parameters and remained stable in the in vitro metabolism. These findings indicate that 6k warrants further in vivo pharmacokinetic and pharmacodynamics investigations.
    Keywords:  Apoptosis; Aurora kinase A/B inhibitors; Docking; Metabolic stability
    DOI:  https://doi.org/10.1016/j.ejmech.2024.116917
  9. bioRxiv. 2024 Sep 26. pii: 2024.09.24.614821. [Epub ahead of print]
    The formation and propagation of human Robertsonian chromosomes.
    Leonardo Gomes de Lima, Andrea Guarracino, Sergey Koren, Tamara Potapova, Sean McKinney, Arang Rhie, Steven J Solar, Chris Seidel, Brandon Fagen, Brian P Walenz, Gerard G Bouffard, Shelise Y Brooks, Michael Peterson, Kate Hall, Juyun Crawford, Alice C Young, Brandon D Pickett, Erik Garrison, Adam M Phillippy, Jennifer L Gerton.
      Robertsonian chromosomes are a type of variant chromosome found commonly in nature. Present in one in 800 humans, these chromosomes can underlie infertility, trisomies, and increased cancer incidence. Recognized cytogenetically for more than a century, their origins have remained mysterious. Recent advances in genomics allowed us to assemble three human Robertsonian chromosomes completely. We identify a common breakpoint and epigenetic changes in centromeres that provide insight into the formation and propagation of common Robertsonian translocations. Further investigation of the assembled genomes of chimpanzee and bonobo highlights the structural features of the human genome that uniquely enable the specific crossover event that creates these chromosomes. Resolving the structure and epigenetic features of human Robertsonian chromosomes at a molecular level paves the way to understanding how chromosomal structural variation occurs more generally, and how chromosomes evolve.
    DOI:  https://doi.org/10.1101/2024.09.24.614821
  10. Nano Lett. 2024 Oct 08.
    Probing the Nanonewton Mitotic Cell Deformation Force by Ion-Resonance-Enhanced Photonics Force Microscopy.
    Xiangjun Di, Dejiang Wang, Xuchen Shan, Lei Ding, Zhaoxiang Zhong, Chaohao Chen, Dajing Wang, Zhiyong Song, Jianyun Wang, Qian Peter Su, Shuhua Yue, Min Zhang, Faliang Cheng, Fan Wang.
      Mechanical forces are essential for regulating dynamic changes in cellular activities. A comprehensive understanding of these forces is imperative for unraveling fundamental mechanisms. Here, we develop a microprobe capable of facilitating the measurement of biological forces up to nanonewton levels in living cells. This probe is designed by coating the core of anatase titania particles with amorphous titania and silica shells and an upconversion nanoparticles (UCNPs) layer. Leveraging both antireflection and ion resonance effects from the shells, the optically trapped probe attains a maximum lateral optical trap stiffness of 14.24 pN μm-1 mW-1, surpassing the best reported value by a factor of 3. Employing this advanced probe in a photonic force microscope, we determine the elasticity modulus of mitotic HeLa cells as 1.27 ± 0.3 kPa. Nanonewton probes offer the potential to explore 3D cellular mechanics with unparalleled precision and spatial resolution, fostering a deeper understanding of the underlying biomechanical mechanisms.
    Keywords:  Cell stiffness; Nanonewton force; Titania particles; Upconversion nanoparticles (UCNPs)
    DOI:  https://doi.org/10.1021/acs.nanolett.4c03610
  11. Genes Cells. 2024 Oct 08.
    Cellular and molecular mechanisms of asymmetric stem cell division in tissue homeostasis.
    Sema Bolkent.
      The asymmetric cell division determines cell diversity and distinct sibling cell fates by mechanisms linked to mitosis. Many adult stem cells divide asymmetrically to balance self-renewal and differentiation. The process of asymmetric cell division involves an axis of polarity and, second, the localization of cell fate determinants at the cell poles. Asymmetric division of stem cells is achieved by intrinsic and extrinsic fate determinants such as signaling molecules, epigenetics factors, molecules regulating gene expression, and polarized organelles. At least some stem cells perform asymmetric and symmetric cell divisions during development. Asymmetric division ensures that the number of stem cells remains constant throughout life. The asymmetric division of stem cells plays an important role in biological events such as embryogenesis, tissue regeneration and carcinogenesis. This review summarizes recent advances in the regulation of asymmetric stem cell division in model organisms.
    Keywords:  asymmetric cell division; diseases; fate determinants; molecular mechanisms; stem cell
    DOI:  https://doi.org/10.1111/gtc.13172
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