bims-micesi 2024-07-28 papers

bims-micesi

Biomed News

on Mitotic cell signalling

Issue of 2024–07–28
six papers selected by
Valentina Piano, Uniklinik Köln

Plasticity of the mitotic spindle in response to karyotype variation.
Argonaute CSR-1 restricts holocentromere protein CENP-A/HCP-3 localization.
Overexpression of BubR1 Mitotic Checkpoint Protein Predicts Short Survival and Influences the Progression of Cholangiocarcinoma.
FOXM1 requires IDH1 for late genes expression in mitotic cells.
Treatments with Diquat Reveal the Relationship between Protein Phosphatases (PP2A) and Oxidative Stress during Mitosis in Arabidopsis thaliana Root Meristems.
Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer.

Curr Biol. 2024 Jul 17. pii: S0960-9822(24)00842-X. [Epub ahead of print]

Plasticity of the mitotic spindle in response to karyotype variation.

Preethi Kunchala, Joseph M Varberg, Eileen O'Toole, Jennifer Gardner, Sarah E Smith, Melainia McClain, Sue L Jaspersen, R Scott Hawley, Jennifer L Gerton.

  Karyotypes, composed of chromosomes, must be accurately partitioned by the mitotic spindle for optimal cell health. However, it is unknown how underlying characteristics of karyotypes, such as chromosome number and size, govern the scaling of the mitotic spindle to ensure accurate chromosome segregation and cell proliferation. We utilize budding yeast strains engineered with fewer chromosomes, including just two "mega chromosomes," to study how spindle size and function are responsive to, and scaled by, karyotype. We determined that deletion and overexpression of spindle-related genes are detrimental to the growth of strains with two chromosomes, suggesting that mega chromosomes exert altered demands on the spindle. Using confocal microscopy, we demonstrate that cells with fewer but longer chromosomes have smaller spindle pole bodies, fewer microtubules, and longer spindles. Moreover, using electron tomography and confocal imaging, we observe elongated, bent anaphase spindles with fewer core microtubules in strains with mega chromosomes. Cells harboring mega chromosomes grow more slowly, are delayed in mitosis, and a subset struggle to complete chromosome segregation. We propose that the karyotype of the cell dictates the microtubule number, type, spindle pole body size, and spindle length, subsequently influencing the dynamics of mitosis, such as the rate of spindle elongation and the velocity of pole separation. Taken together, our results suggest that mitotic spindles are highly plastic ultrastructures that can accommodate and adjust to a variety of karyotypes, even within a species.

Keywords:  anaphase; centromere; chromosome; chromosome segregation; chromosome size; karyotype; metaphase; microtubule; mitosis; spindle; spindle pole body; tomography

DOI:  https://doi.org/10.1016/j.cub.2024.06.058
J Cell Sci. 2024 Jul 22. pii: jcs.261895. [Epub ahead of print]

Argonaute CSR-1 restricts holocentromere protein CENP-A/HCP-3 localization.

Charmaine Yan Yu Wong, Hok Ning Tsui, Yue Wang, Karen Wing Yee Yuen.

  Chromosome segregation errors caused by centromere malfunction can lead to chromosome instability and aneuploidy. In Caenorhabditis elegans, the Argonaute protein CSR-1 is essential for proper chromosome segregation, though the specific mechanisms are not fully understood. Here we investigated how CSR-1 regulates centromere and kinetochore function in C. elegans embryos. We found that the depletion of CSR-1 results in defects in mitotic progression and chromosome positioning relative to the spindle pole. CSR-1 knockdown does not affect centromeric histone H3 variant CENP-A/HCP-3 mRNA and protein levels, but increases the localization of HCP-3 and some kinetochore proteins onto the mitotic chromosomes. Such elevation of chromatin HCP-3 localization depends on the CSR-1 RNAi pathway upstream factor EGO-1 and CSR-1's PIWI domain activity. Our results suggest that CSR-1 restricts HCP-3 level at the holocentromeres, prevents erroneous kinetochore assembly, and thereby promotes accurate chromosome segregation. Our work sheds light on CSR-1's role in regulating deposition of HCP-3 on chromatin and centromere function in the embryos.

Keywords:  CENP-A/HCP-3 localization; Centromere; Chromosome segregation; Kinetochore; RNA interference pathway

DOI:  https://doi.org/10.1242/jcs.261895
Biomedicines. 2024 Jul 19. pii: 1611. [Epub ahead of print]12(7):

Overexpression of BubR1 Mitotic Checkpoint Protein Predicts Short Survival and Influences the Progression of Cholangiocarcinoma.

Nongnapas Pokaew, Piya Prajumwongs, Kulthida Vaeteewoottacharn, Sopit Wongkham, Chawalit Pairojkul, Kanlayanee Sawanyawisuth.

  Budding Uninhibited by Benzimidazole-Related 1 (BubR1) or BUB1 Mitotic Checkpoint Serine/Threonine Kinase B (BUB1B) is an essential component of the spindle assembly checkpoint (SAC), which controls chromosome separation during mitosis. Overexpression of BubR1 has been associated with the progression of various cancers. This study demonstrated that high expression of BubR1 correlated with cholangiocarcinogenesis in a hamster cholangiocarcinoma (CCA) model and was associated with shorter survival in patients with CCA. Co-expression of BubR1 and MPS1, which is a SAC-related protein, indicated a shorter survival rate in patients with CCA. Knockdown of BubR1 expression by specific siRNA (siBubR1) significantly decreased cell proliferation and colony formation while inducing apoptosis in CCA cell lines. In addition, suppression of BubR1 inhibited migration and invasion abilities via epithelial-mesenchymal transition (EMT). A combination of siBubR1 and chemotherapeutic drugs showed synergistic effects in CCA cell lines. Taken together, this finding suggested that BubR1 had oncogenic functions, which influenced CCA progression. Suppression of BubR1 might be an alternative option for CCA treatment.

Keywords:  BUB1B; BubR1; cholangiocarcinoma; mitotic checkpoint

DOI:  https://doi.org/10.3390/biomedicines12071611
Histochem Cell Biol. 2024 Jul 22.

FOXM1 requires IDH1 for late genes expression in mitotic cells.

Balabhaskararao Kancharana, Hashnu Dutta, Nishant Jain.

  Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that converts isocitrate to α-ketoglutarate in cells. However, research on IDH1 is more focused on the metabolite D-2-hydroxyglutarate than the cellular roles of the IDH1 protein. Metabolic enzymes can moonlight by participating in diverse cellular processes in cancer cells. This moonlighting function of the metabolic enzymes can contribute to changes in gene expression. It is unknown whether IDH1 associates with any transcription factor. We asked whether IDH1 coordinates with forkhead box protein M1 (FOXM1) in mitotic cells to regulate late genes expression. We found that depletion of IDH1 reduces canonical FOXM1-target expression in mitotic cells. Also, IDH1 binds to FOXM1 and a subset of MuvB proteins, Lin-9 and Lin-54, in mitotic cells. Based on these observations, we suggest that IDH1 coordinates with FOXM1 in mitotic cells to regulate late genes expression.

Keywords:  FOXM1; IDH1; Lin-54; Lin-9; Mitosis; MuvB

DOI:  https://doi.org/10.1007/s00418-024-02307-8
Plants (Basel). 2024 Jul 10. pii: 1896. [Epub ahead of print]13(14):

Treatments with Diquat Reveal the Relationship between Protein Phosphatases (PP2A) and Oxidative Stress during Mitosis in Arabidopsis thaliana Root Meristems.

Adrienn Kelemen, Tamás Garda, Zoltán Kónya, Ferenc Erdődi, László Ujlaky-Nagy, Gabriella Petra Juhász, Csongor Freytag, Márta M-Hamvas, Csaba Máthé.

  Reversible protein phosphorylation regulates various cellular mechanisms in eukaryotes by altering the conformation, activity, localization, and stability of substrate proteins. In Arabidopsis thaliana root meristems, histone post-translational modifications are crucial for proper cell division, and they are also involved in oxidative stress signaling. To investigate the link between reactive oxygen species (ROS) and mitosis, we treated various Arabidopsis genotypes, including wild-types and mutants showing dysfunctional PP2A, with the ROS-inducing herbicide diquat (DQ). Studying the c3c4 double catalytic subunit mutant and fass regulatory subunit mutants of PP2A provided insights into phosphorylation-dependent mitotic processes. DQ treatment reduced mitotic activity in all genotypes and caused early mitotic arrest in PP2A mutants, likely due to oxidative stress-induced damage to essential mitotic processes. DQ had a minimal effect on reversible histone H3 phosphorylation in wild-type plants but significantly decreased phospho-histone H3 levels in PP2A mutants. Following drug treatment, the phosphatase activity decreased only in the stronger phenotype mutant plants (fass-5 and c3c4). Our findings demonstrate that (i) the studied PP2A loss-of-function mutants are more sensitive to increased intracellular ROS and (ii) DQ has indirect altering effects of mitotic activities and histone H3 phosphorylation. All these findings underscore the importance of PP2A in stress responses.

Keywords:  Arabidopsis thaliana; C3-C4; FASS; PP2A; diquat; histone H3 phosphorylation; mitosis; protein phosphatases; reactive oxygen species (ROS)

DOI:  https://doi.org/10.3390/plants13141896
Cancer Res. 2024 Jul 22.

Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer.

Katrina M Piemonte, Natasha N Ingles, Kristen L Weber Bonk, Mitchell J Valentine, Parth R Majmudar, Salendra Singh, Ruth A Keri.

Clinical trials examining broad-spectrum Src family kinase (SFK) inhibitors revealed significant dose-limiting toxicities, preventing advancement for solid tumors. SFKs are functionally heterogeneous, thus targeting individual members is a potential strategy to elicit anti-tumor efficacy while avoiding toxicity. Here, we identified that YES1 is the most highly overexpressed SFK in triple negative breast cancer (TNBC) and is associated with poor patient outcomes. Disrupting YES1, genetically or pharmacologically, induced aberrant mitosis, centrosome amplification, multi-polar spindles, and chromosomal instability (CIN). Mechanistically, YES1 sustained FOXM1 protein levels and elevated expression of FOXM1 target genes that control centrosome function and are essential for effective and accurate mitotic progression. In both in vitro and in vivo TNBC models, YES1 suppression potentiated the efficacy of taxanes, cornerstone drugs for TNBC that require elevated CIN for efficacy. Clinically, elevated expression of YES1 was associated with worse overall survival of TNBC patients treated with taxane and anthracycline combination regimens. Together, this study demonstrates that YES1 is an essential regulator of genome stability in TNBC that can be leveraged to improve taxane efficacy.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2558