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Trends in Cell Biology Feb 2021Autophagy and cap-dependent mRNA translation are tightly regulated by the mechanistic target of rapamycin complex 1 (mTORC1) signalling complex in response to nutrient... (Review)
Review
Autophagy and cap-dependent mRNA translation are tightly regulated by the mechanistic target of rapamycin complex 1 (mTORC1) signalling complex in response to nutrient availability. However, the regulation of these processes, and mTORC1 itself, is different during mitosis, and this has remained an area of significant controversy; for example, studies have argued that autophagy is either repressed or highly active during mitosis. Recent studies have shown that autophagy initiation is repressed, and cap-dependent mRNA translation is maintained during mitosis despite mTORC1 activity being repressed. This is achieved in large part by a switch from mTORC1- to cyclin-dependent kinase 1 (CDK1)-mediated regulation. Here, we review the history and recent advances and seek to present a unifying model to inform the future study of autophagy and mTORC1 during mitosis.
Topics: Autophagy; CDC2 Protein Kinase; Cell Line; Cell Line, Tumor; Humans; Mechanistic Target of Rapamycin Complex 1; Mitosis; Phosphorylation; Protein Biosynthesis; Signal Transduction
PubMed: 33272830
DOI: 10.1016/j.tcb.2020.11.001 -
Oncogene May 2022Proper progression through the cell-division cycle is critical to normal development and homeostasis and is necessarily misregulated in cancer. The key to cell-cycle... (Review)
Review
Proper progression through the cell-division cycle is critical to normal development and homeostasis and is necessarily misregulated in cancer. The key to cell-cycle regulation is the control of two waves of transcription that occur at the onset of DNA replication (S phase) and mitosis (M phase). MuvB complexes play a central role in the regulation of these genes. When cells are not actively dividing, the MuvB complex DREAM represses G1/S and G2/M genes. Remarkably, MuvB also forms activator complexes together with the oncogenic transcription factors B-MYB and FOXM1 that are required for the expression of the mitotic genes in G2/M. Despite this essential role in the control of cell division and the relationship to cancer, it has been unclear how MuvB complexes inhibit and stimulate gene expression. Here we review recent discoveries of MuvB structure and molecular interactions, including with nucleosomes and other chromatin-binding proteins, which have led to the first mechanistic models for the biochemical function of MuvB complexes.
Topics: Cell Cycle; Cell Cycle Proteins; Humans; Mitosis; Neoplasms; Trans-Activators
PubMed: 35468940
DOI: 10.1038/s41388-022-02321-x -
Seminars in Cell & Developmental Biology Sep 2021
Topics: Animals; Cell Biology; Mitosis
PubMed: 34172396
DOI: 10.1016/j.semcdb.2021.06.014 -
Cells Apr 2022A conserved feature of virtually all higher eukaryotes is that the centromeres are embedded in heterochromatin. Here we provide evidence that this tight association... (Review)
Review
A conserved feature of virtually all higher eukaryotes is that the centromeres are embedded in heterochromatin. Here we provide evidence that this tight association between pericentric heterochromatin and the centromere is essential for proper metaphase exit and progression into telophase. Analysis of chromosome rearrangements that separate pericentric heterochromatin and centromeres indicates that they must remain associated in order to balance Cohesin/DNA catenation-based binding forces and centromere-based pulling forces during the metaphase-anaphase transition. In addition, a centromere embedded in heterochromatin facilitates nuclear envelope assembly around the entire complement of segregating chromosomes. Because the nuclear envelope initially forms on pericentric heterochromatin, nuclear envelope formation proceeds from the pole, thus providing time for incorporation of lagging and trailing chromosome arms into the newly formed nucleus. Additional analysis of noncanonical mitoses provides further insights into the functional significance of the tight association between heterochromatin and centromeres.
Topics: Anaphase; Centromere; Heterochromatin; Metaphase; Mitosis
PubMed: 35406810
DOI: 10.3390/cells11071247 -
Biochemical Pharmacology Aug 2021Dysregulation of cell cycle progression is a hallmark of cancer cells. In recent years, efforts have been devoted to the development of new therapies that target... (Review)
Review
Dysregulation of cell cycle progression is a hallmark of cancer cells. In recent years, efforts have been devoted to the development of new therapies that target proteins involved in cell cycle regulation and mitosis. Novel targeted antimitotic drugs include inhibitors of aurora kinase family, polo-like kinase 1, Mps1, Eg5, CENP-5 and the APC/cyclosome complex. While certain new inhibitors reached the clinical trial stage, most were discontinued due to negative results. However, these therapies should not be readily dismissed. Based on recent advances concerning their mechanisms of action, new strategies could be devised to increase their efficacy and promote further clinical trials. Here we discuss three main lines of action to empower these therapeutic approaches: increasing cell death signals during mitotic arrest, targeting senescent cells and facilitating antitumor immune response through immunogenic cell death (ICD).
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Mitosis; Neoplasms
PubMed: 34129859
DOI: 10.1016/j.bcp.2021.114655 -
Chromosoma Jun 2023A report on the 5th International Chromosome Stability Meeting, Thiruvananthapuram, India, Dec. 14-18, 2022. (Review)
Review
A report on the 5th International Chromosome Stability Meeting, Thiruvananthapuram, India, Dec. 14-18, 2022.
Topics: Centromere; Kinetochores; Meiosis; Mitosis; Chromosome Segregation
PubMed: 37145129
DOI: 10.1007/s00412-023-00795-6 -
Advances in Anatomy, Embryology, and... 2022As major accomplishments and breakthroughs in centrosome research had been achieved by Theodor Boveri in reproductive cells with the invertebrate sea urchin being an...
As major accomplishments and breakthroughs in centrosome research had been achieved by Theodor Boveri in reproductive cells with the invertebrate sea urchin being an ideal model system for such studies on fertilization, cell division, and embryo development, these studies also gave rise to Boveri's brilliant concept regarding cancer cells. He discovered that eggs fertilized with two sperm resulted in tripolar mitosis and abnormal cell division, similar to cells observed in cancer tissue.
Topics: Animals; Male; Semen; Centrosome; Fertilization; Sea Urchins; Mitosis; Neoplasms
PubMed: 36525110
DOI: 10.1007/978-3-031-20848-5_4 -
Biochemical Pharmacology Sep 2019Mitosis ensures accurate segregation of duplicated DNA through tight regulation of chromosome condensation, bipolar spindle assembly, chromosome alignment in the... (Review)
Review
Mitosis ensures accurate segregation of duplicated DNA through tight regulation of chromosome condensation, bipolar spindle assembly, chromosome alignment in the metaphase plate, chromosome segregation and cytokinesis. Poly(ADP-ribose) polymerases (PARPs), in particular PARP1, PARP2, PARP3, PARP5a (TNKS1), as well as poly(ADP-ribose) glycohydrolase (PARG), regulate different mitotic functions, including centrosome function, mitotic spindle assembly, mitotic checkpoints, telomere length and telomere cohesion. PARP depletion or inhibition give rise to various mitotic defects such as centrosome amplification, multipolar spindles, chromosome misalignment, premature loss of cohesion, metaphase arrest, anaphase DNA bridges, lagging chromosomes, and micronuclei. As the mechanisms of PARP1/2 inhibitor-mediated cell death are being progressively elucidated, it is becoming clear that mitotic defects caused by PARP1/2 inhibition arise due to replication stress and DNA damage in S phase. As it stands, entrapment of inactive PARP1/2 on DNA phenocopies replication stress through accumulation of unresolved replication intermediates, double-stranded DNA breaks (DSBs) and incorrectly repaired DSBs, which can be transmitted from S phase to mitosis and instigate various mitotic defects, giving rise to both numerical and structural chromosomal aberrations. Cancer cells have increased levels of replication stress, which makes them particularly susceptible to a combination of agents that compromise replication fork stability. Indeed, combining PARP1/2 inhibitors with genetic deficiencies in DNA repair pathways, DNA-damaging agents, ATR and other cell cycle checkpoint inhibitors has yielded synergistic effects in killing cancer cells. Here I provide a comprehensive overview of the mitotic functions of PARPs and PARG, mitotic phenotypes induced by their depletion or inhibition, as well as the therapeutic relevance of targeting mitotic cells by directly interfering with mitotic functions or indirectly through replication stress.
Topics: Animals; DNA Damage; DNA Repair; Humans; Mitosis; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 30910692
DOI: 10.1016/j.bcp.2019.03.028 -
Methods in Molecular Biology (Clifton,... 2021The completely homozygous genetic background of doubled haploids (DHs) has many applications in breeding programs and research studies. Haploid induction and chromosome... (Review)
Review
The completely homozygous genetic background of doubled haploids (DHs) has many applications in breeding programs and research studies. Haploid induction and chromosome doubling of induced haploids are the two main steps of doubled haploid creation. Both steps have their own complexities. Chromosome doubling of induced haploids may happen spontaneously, although usually at a low rate. Therefore, artificial/induced chromosome doubling of haploid cells/plantlets is necessary to produce DHs at an acceptable level. The most common method is using some mitotic spindle poisons that target the organization of the microtubule system. Colchicine is a well-known and widely used antimitotic. However, there are substances alternative to colchicine in terms of efficiency, toxicity, safety, and genetic stability, which can be applied in in vitro and in vivo pathways. Both pathways have their own advantages and disadvantages. However, in vitro-induced chromosome doubling has been much preferred in recent years, maybe because of the dual effect of antimitotic agents (haploid induction and chromosome doubling) in just one step, and the reduced generation of chimeras. Plant genotype, the developmental stage of initial haploids, and type-concentration-duration of application of antimitotic agents, are top influential parameters on chromosome doubling efficiency. In this review, we highlight different aspects related to antimitotic agents and to plant parameters for successful chromosome doubling and high DH yield.
Topics: Chromosomes, Plant; Crops, Agricultural; Mitosis; Plant Breeding
PubMed: 34270027
DOI: 10.1007/978-1-0716-1315-3_5 -
Nature Communications Sep 2019The centrosome is the master orchestrator of mitotic spindle formation and chromosome segregation in animal cells. Centrosome abnormalities are frequently observed in...
The centrosome is the master orchestrator of mitotic spindle formation and chromosome segregation in animal cells. Centrosome abnormalities are frequently observed in cancer, but little is known of their origin and about pathways affecting centrosome homeostasis. Here we show that autophagy preserves centrosome organization and stability through selective turnover of centriolar satellite components, a process we termed doryphagy. Autophagy targets the satellite organizer PCM1 by interacting with GABARAPs via a C-terminal LIR motif. Accordingly, autophagy deficiency results in accumulation of large abnormal centriolar satellites and a resultant dysregulation of centrosome composition. These alterations have critical impact on centrosome stability and lead to mitotic centrosome fragmentation and unbalanced chromosome segregation. Our findings identify doryphagy as an important centrosome-regulating pathway and bring mechanistic insights to the link between autophagy dysfunction and chromosomal instability. In addition, we highlight the vital role of centriolar satellites in maintaining centrosome integrity.
Topics: Autophagy; Cell Cycle; Cell Line, Tumor; Centrioles; Centrosome; Chromatography, Liquid; Humans; Immunoblotting; Magnetic Resonance Spectroscopy; Mass Spectrometry; Microscopy, Fluorescence; Microtubules; Mitosis; Molecular Dynamics Simulation
PubMed: 31519908
DOI: 10.1038/s41467-019-12094-9