International Journal of Molecular Sciences

20 pages, 3165 KiB

Open AccessArticle

Essential Role of COPII Proteins in Maintaining the Contractile Ring Anchoring to the Plasma Membrane during Cytokinesis in Drosophila Male Meiosis

by Yoshiki Matsuura, Kana Kaizuka and Yoshihiro H. Inoue

Int. J. Mol. Sci. 2024, 25(8), 4526; https://doi.org/10.3390/ijms25084526 - 20 Apr 2024

Cited by 1 | Viewed by 1998

Abstract

Coatomer Protein Complex-II (COPII) mediates anterograde vesicle transport from the endoplasmic reticulum (ER) to the Golgi apparatus. Here, we report that the COPII coatomer complex is constructed dependent on a small GTPase, Sar1, in spermatocytes before and during Drosophila male meiosis. COPII-containing foci [...] Read more.

Coatomer Protein Complex-II (COPII) mediates anterograde vesicle transport from the endoplasmic reticulum (ER) to the Golgi apparatus. Here, we report that the COPII coatomer complex is constructed dependent on a small GTPase, Sar1, in spermatocytes before and during Drosophila male meiosis. COPII-containing foci co-localized with transitional endoplasmic reticulum (tER)-Golgi units. They showed dynamic distribution along astral microtubules and accumulated around the spindle pole, but they were not localized on the cleavage furrow (CF) sites. The depletion of the four COPII coatomer subunits, Sec16, or Sar1 that regulate COPII assembly resulted in multinucleated cell production after meiosis, suggesting that cytokinesis failed in both or either of the meiotic divisions. Although contractile actomyosin and anilloseptin rings were formed once plasma membrane ingression was initiated, they were frequently removed from the plasma membrane during furrowing. We explored the factors conveyed toward the CF sites in the membrane via COPII-mediated vesicles. DE-cadherin-containing vesicles were formed depending on Sar1 and were accumulated in the cleavage sites. Furthermore, COPII depletion inhibited de novo plasma membrane insertion. These findings suggest that COPII vesicles supply the factors essential for the anchoring and/or constriction of the contractile rings at cleavage sites during male meiosis in Drosophila. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

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36 pages, 907 KiB

Open AccessReview

Non-Coding RNAs of Mitochondrial Origin: Roles in Cell Division and Implications in Cancer

by Roberto Piergentili and Stefano Sechi

Int. J. Mol. Sci. 2024, 25(13), 7498; https://doi.org/10.3390/ijms25137498 - 8 Jul 2024

Cited by 5 | Viewed by 2924

Abstract

Non-coding RNAs (ncRNAs) are a heterogeneous group, in terms of structure and sequence length, consisting of RNA molecules that do not code for proteins. These ncRNAs have a central role in the regulation of gene expression and are virtually involved in every process [...] Read more.

Non-coding RNAs (ncRNAs) are a heterogeneous group, in terms of structure and sequence length, consisting of RNA molecules that do not code for proteins. These ncRNAs have a central role in the regulation of gene expression and are virtually involved in every process analyzed, ensuring cellular homeostasis. Although, over the years, much research has focused on the characterization of non-coding transcripts of nuclear origin, improved bioinformatic tools and next-generation sequencing (NGS) platforms have allowed the identification of hundreds of ncRNAs transcribed from the mitochondrial genome (mt-ncRNA), including long non-coding RNA (lncRNA), circular RNA (circRNA), and microRNA (miR). Mt-ncRNAs have been described in diverse cellular processes such as mitochondrial proteome homeostasis and retrograde signaling; however, the function of the majority of mt-ncRNAs remains unknown. This review focuses on a subgroup of human mt-ncRNAs whose dysfunction is associated with both failures in cell cycle regulation, leading to defects in cell growth, cell proliferation, and apoptosis, and the development of tumor hallmarks, such as cell migration and metastasis formation, thus contributing to carcinogenesis and tumor development. Here we provide an overview of the mt-ncRNAs/cancer relationship that could help the future development of new biomedical applications in the field of oncology. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

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21 pages, 5355 KiB

Open AccessArticle

Protein Kinase C-Delta Mediates Cell Cycle Reentry and Apoptosis Induced by Amyloid-Beta Peptide in Post-Mitotic Cortical Neurons

by Ming-Hsuan Wu, A-Ching Chao, Yi-Heng Hsieh, You Lien, Yi-Chun Lin and Ding-I Yang

Int. J. Mol. Sci. 2024, 25(17), 9626; https://doi.org/10.3390/ijms25179626 - 5 Sep 2024

Cited by 2 | Viewed by 1380

Abstract

Amyloid-beta peptide (Aβ) is a neurotoxic constituent of senile plaques in the brains of Alzheimer’s disease (AD) patients. The detailed mechanisms by which protein kinase C-delta (PKCδ) contributes to Aβ toxicity is not yet entirely understood. Using fully differentiated primary rat cortical neurons, [...] Read more.

Amyloid-beta peptide (Aβ) is a neurotoxic constituent of senile plaques in the brains of Alzheimer’s disease (AD) patients. The detailed mechanisms by which protein kinase C-delta (PKCδ) contributes to Aβ toxicity is not yet entirely understood. Using fully differentiated primary rat cortical neurons, we found that inhibition of Aβ25-35-induced PKCδ increased cell viability with restoration of neuronal morphology. Using cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) as the respective markers for the G1-, S-, and G2/M-phases, PKCδ inhibition mitigated cell cycle reentry (CCR) and subsequent caspase-3 cleavage induced by both Aβ25-35 and Aβ1-42 in the post-mitotic cortical neurons. Upstream of PKCδ, signal transducers and activators of transcription (STAT)-3 mediated PKCδ induction, CCR, and caspase-3 cleavage upon Aβ exposure. Downstream of PKCδ, aberrant neuronal CCR was triggered by overactivating cyclin-dependent kinase-5 (CDK5) via calpain2-dependent p35 cleavage into p25. Finally, PKCδ and CDK5 also contributed to Aβ25-35 induction of p53-upregulated modulator of apoptosis (PUMA) in cortical neurons. Together, we demonstrated that, in the post-mitotic neurons exposed to Aβs, STAT3-dependent PKCδ expression triggers calpain2-mediated p35 cleavage into p25 to overactivate CDK5, thus leading to aberrant CCR, PUMA induction, caspase-3 cleavage, and ultimately apoptosis. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

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11 pages, 3503 KiB

Open AccessArticle

Alignment of a Trivalent Chromosome on the Metaphase Plate Is Associated with Differences in Microtubule Density at Each Kinetochore

by Ashley B. Borseth, Hedyeh D. Kianersi, Paige Galloway, Grace Gercken, Emily L. Stowe, Marie Pizzorno and Leocadia V. Paliulis

Int. J. Mol. Sci. 2024, 25(19), 10719; https://doi.org/10.3390/ijms251910719 - 5 Oct 2024

Viewed by 1231

Abstract

Chromosome alignment on the metaphase plate is a conserved phenomenon and is an essential function for correct chromosome segregation for many organisms. Organisms with naturally-occurring trivalent chromosomes provide a useful system for understanding how chromosome alignment is evolutionarily regulated, as they align on [...] Read more.

Chromosome alignment on the metaphase plate is a conserved phenomenon and is an essential function for correct chromosome segregation for many organisms. Organisms with naturally-occurring trivalent chromosomes provide a useful system for understanding how chromosome alignment is evolutionarily regulated, as they align on the spindle with one kinetochore facing one pole and two facing the opposite pole. We studied chromosome alignment in a praying mantid that has not been previously studied chromosomally, the giant shield mantis Rhombodera megaera. R. megaera has a chromosome number of 2n = 27 in males. Males have X₁, X₂, and Y chromosomes that combine to form a trivalent in meiosis I. Using live-cell imaging of spermatocytes in meiosis I, we document that sex trivalent Y chromosomes associate with one spindle pole and the two X chromosomes associate with the opposing spindle pole. Sex trivalents congress alongside autosomes, align with them on the metaphase I plate, and then the component chromosomes segregate alongside autosomes in anaphase I. Immunofluorescence imaging and quantification of brightness of kinetochore–microtubule bundles suggest that the X₁ and X₂ kinetochores are associated with fewer microtubules than the Y kinetochore, likely explaining the alignment of the sex trivalent at the spindle equator with autosomes. These observations in R. megaera support the evolutionary significance of the metaphase alignment of chromosomes and provide part of the explanation for how this alignment is achieved. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

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15 pages, 8447 KiB

Open AccessArticle

MAD2L2 Dimerization Is Not Essential for Mitotic Regulation

by Nomi Barda, Philippa Jennifer Ayiku, Amit Bar-on, Sahar Movshovitz and Tamar Listovsky

Int. J. Mol. Sci. 2024, 25(21), 11485; https://doi.org/10.3390/ijms252111485 - 25 Oct 2024

Viewed by 978

Abstract

MAD2L2 is a small HORMA domain protein that plays a crucial role in DNA repair and mitosis. In both TLS and shieldin, the dimerization of MAD2L2 via its HORMA domain is critical for the stability and function of these complexes. However, in mitosis, [...] Read more.

MAD2L2 is a small HORMA domain protein that plays a crucial role in DNA repair and mitosis. In both TLS and shieldin, the dimerization of MAD2L2 via its HORMA domain is critical for the stability and function of these complexes. However, in mitosis, the dimerization state of MAD2L2 remains unknown. To assess the importance of MAD2L2’s dimerization during mitosis, we utilized CRISPR/Cas9 to generate MAD2L2 knockout cells, which were subsequently complemented with MAD2L2 species carrying different dimer-disrupting point mutations. We assessed the ability of these MAD2L2 dimer-disrupting mutants to regulate mitosis by evaluating early mitotic events and mitotic fidelity. Our findings indicate that MAD2L2 can function in its monomeric form during mitosis, suggesting that MAD2L2 homodimerization is dispensable for early mitotic regulation. Furthermore, our results suggest that the binding of CDH1 to MAD2L2 is a key regulating factor in mitosis that may actively prevent the formation of MAD2L2 dimers, thereby shifting the cellular balance toward MAD2L2-CDH1 interaction. Thus, the equilibrium between the monomeric and dimeric forms of MAD2L2 is an important cellular factor regulating the MAD2L2-containing complexes. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

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31 pages, 4693 KiB

Open AccessReview

Decoding the Nucleolar Role in Meiotic Recombination and Cell Cycle Control: Insights into Cdc14 Function

by Paula Alonso-Ramos and Jesús A. Carballo

Int. J. Mol. Sci. 2024, 25(23), 12861; https://doi.org/10.3390/ijms252312861 - 29 Nov 2024

Viewed by 1484

Abstract

The cell cycle, essential for growth, reproduction, and genetic stability, is regulated by a complex network of cyclins, Cyclin-Dependent Kinases (CDKs), phosphatases, and checkpoints that ensure accurate cell division. CDKs and phosphatases are crucial for controlling cell cycle progression, with CDKs promoting it [...] Read more.

The cell cycle, essential for growth, reproduction, and genetic stability, is regulated by a complex network of cyclins, Cyclin-Dependent Kinases (CDKs), phosphatases, and checkpoints that ensure accurate cell division. CDKs and phosphatases are crucial for controlling cell cycle progression, with CDKs promoting it and phosphatases counteracting their activity to maintain balance. The nucleolus, as a biomolecular condensate, plays a key regulatory role by serving as a hub for ribosome biogenesis and the sequestration and release of various cell cycle regulators. This phase separation characteristic of the nucleolus is vital for the specific and timely release of Cdc14, required for most essential functions of phosphatase in the cell cycle. While mitosis distributes chromosomes to daughter cells, meiosis is a specialized division process that produces gametes and introduces genetic diversity. Central to meiosis is meiotic recombination, which enhances genetic diversity by generating crossover and non-crossover products. This process begins with the introduction of double-strand breaks, which are then processed by numerous repair enzymes. Meiotic recombination and progression are regulated by proteins and feedback mechanisms. CDKs and polo-like kinase Cdc5 drive recombination through positive feedback, while phosphatases like Cdc14 are crucial for activating Yen1, a Holliday junction resolvase involved in repairing unresolved recombination intermediates in both mitosis and meiosis. Cdc14 is released from the nucleolus in a regulated manner, especially during the transition between meiosis I and II, where it helps inactivate CDK activity and promote proper chromosome segregation. This review integrates current knowledge, providing a synthesis of these interconnected processes and an overview of the mechanisms governing cell cycle regulation and meiotic recombination. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

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13 pages, 3250 KiB

Open AccessArticle

p31^Comet Splice Variants Induce Distinct Spindle Assembly Checkpoint Dynamics due to Their Unique N-Termini

by Luke Scarberry, Garrett Thesing, Kevin Brennan, Madison Williams and Matthew K. Summers

Int. J. Mol. Sci. 2025, 26(7), 3089; https://doi.org/10.3390/ijms26073089 - 27 Mar 2025

Viewed by 431

Abstract

The role of p31^Comet in deactivating the spindle assembly checkpoint is well described in the literature; however, the data are all completed using Variant 2 of p31^Comet. p31^Comet is known to be expressed as two different splice variants: Variant [...] Read more.

The role of p31^Comet in deactivating the spindle assembly checkpoint is well described in the literature; however, the data are all completed using Variant 2 of p31^Comet. p31^Comet is known to be expressed as two different splice variants: Variant 1 and Variant 2. Variant 1 contains an additional 32 N-terminal residues compared to Variant 2. We report that Variant 1 exhibits a reduced ability to bind to MAD2 and thus a reduced ability to induce mitotic progression. Additionally, we show that Variant 1 exhibits reduced stability compared to Variant 2. We further show that Variant 1 is uniquely expressed in the Testes, indicating a potentially unique role of Variant 1 in that organ. Overall, we demonstrate the N-terminus of p31^Comet is capable of modulating p31^Comet activity in mitosis. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

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18 pages, 3162 KiB

Open AccessArticle

Controlled Exit from the G2/M Checkpoint in RPE-1 Cells Using RO3306: Enrichment of Phase-Specific Cell Populations for In-Depth Analyses of Mitotic Events

by Teresa Anglada, Núria Pulido-Artola, Marina Rodriguez-Muñoz and Anna Genesca

Int. J. Mol. Sci. 2025, 26(10), 4951; https://doi.org/10.3390/ijms26104951 - 21 May 2025

Viewed by 361

Abstract

Studying the cell cycle is essential for understanding the molecular mechanisms that regulate cell division, growth, and differentiation in living organisms. However, mitosis constitutes only a brief phase of the overall cell cycle, making its analysis challenging in asynchronous cell populations due to [...] Read more.

Studying the cell cycle is essential for understanding the molecular mechanisms that regulate cell division, growth, and differentiation in living organisms. However, mitosis constitutes only a brief phase of the overall cell cycle, making its analysis challenging in asynchronous cell populations due to its transient and dynamic nature. Cell synchronization methods help to enrich populations at specific cell cycle stages, including mitosis, typically by using chemical inhibitors to arrest cells at defined checkpoints. However, many existing protocols rely on combinations of inhibitors that interfere with normal mitotic progression, disrupting dynamics and causing side effects such as chromosome non-disjunction or lagging chromosomes, which limit their applicability. In this study, we present an RO3306 block-and-release strategy to selectively enrich cell populations at defined mitotic stages without compromising cell viability or disrupting their progression to mitotic exit. This approach provides a reliable method for studying mitotic events with high temporal resolution. Furthermore, by preserving mitotic integrity, it offers a valuable framework for investigating the molecular mechanisms of cell division and the processes driving genomic instability in human cells. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

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16 pages, 3791 KiB

Open AccessArticle

Spindle Orientation Regulation Is Governed by Redundant Cortical Mechanosensing and Shape-Sensing Mechanisms

by Rania Hadjisavva and Paris A. Skourides

Int. J. Mol. Sci. 2025, 26(12), 5730; https://doi.org/10.3390/ijms26125730 - 15 Jun 2025

Viewed by 150

Abstract

Spindle orientation (SO) plays a critical role in tissue morphogenesis, homeostasis, and tumorigenesis by ensuring accurate division plane positioning in response to intrinsic and extrinsic cues. While SO has been extensively linked to cell shape sensing and cortical forces, the interplay between shape- [...] Read more.

Spindle orientation (SO) plays a critical role in tissue morphogenesis, homeostasis, and tumorigenesis by ensuring accurate division plane positioning in response to intrinsic and extrinsic cues. While SO has been extensively linked to cell shape sensing and cortical forces, the interplay between shape- and force-sensing mechanisms remains poorly understood. Here, we reveal that SO is governed by two parallel mechanisms that ensure redundancy and adaptability in diverse cellular environments. Using live-cell imaging of cultured cells, we demonstrate that the long prometaphase axis (LPA) is a superior predictor of SO compared to the long interphase axis, reflecting adhesive geometry and force distribution efficiently at prometaphase. Importantly, we uncover a pivotal role for focal adhesion kinase (FAK) in mediating cortical mechanosensing to regulate SO in cells undergoing complete metaphase rounding. We show that in cells with complete metaphase rounding, FAK-dependent force sensing aligns the spindle with the major force vector, ensuring accurate division. Conversely, in cells retaining shape anisotropy during mitosis, a FAK-independent shape-sensing mechanism drives SO. These findings highlight a dual regulatory system for SO, where shape sensing and force sensing operate in parallel to maintain division plane fidelity, shedding light on the mechanisms that enable cells to adapt to diverse physical and mechanical environments. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

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