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Cell Oct 2023Cytoplasmic divisions are thought to rely on nuclear divisions and mitotic signals. We demonstrate in Drosophila embryos that cytoplasm can divide repeatedly without...
Cytoplasmic divisions are thought to rely on nuclear divisions and mitotic signals. We demonstrate in Drosophila embryos that cytoplasm can divide repeatedly without nuclei and mitotic CDK/cyclin complexes. Cdk1 normally slows an otherwise faster cytoplasmic division cycle, coupling it with nuclear divisions, and when uncoupled, cytoplasm starts dividing before mitosis. In developing embryos where CDK/cyclin activity can license mitotic microtubule (MT) organizers like the spindle, cytoplasmic divisions can occur without the centrosome, a principal organizer of interphase MTs. However, centrosomes become essential in the absence of CDK/cyclin activity, implying that the cytoplasm can employ either the centrosome-based interphase or CDK/cyclin-dependent mitotic MTs to facilitate its divisions. Finally, we present evidence that autonomous cytoplasmic divisions occur during unperturbed fly embryogenesis and that they may help extrude mitotically stalled nuclei during blastoderm formation. We postulate that cytoplasmic divisions occur in cycles governed by a yet-to-be-uncovered clock mechanism autonomous from CDK/cyclin complexes.
Topics: Animals; Cell Nucleus; Centrosome; Cyclins; Cytokinesis; Drosophila; Mitosis; Spindle Apparatus; Embryo, Nonmammalian
PubMed: 37832525
DOI: 10.1016/j.cell.2023.09.010 -
Science (New York, N.Y.) Apr 2009It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken...
It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.
Topics: Adult; Aged; Aging; Carbon Radioisotopes; Cell Count; Cell Nucleus; Cell Nucleus Division; Cell Proliferation; Cell Separation; DNA; Echocardiography, Doppler, Color; Humans; Middle Aged; Models, Cardiovascular; Myocytes, Cardiac; Nuclear Weapons; Polyploidy; Radiometric Dating; Stem Cells; Troponin I; Troponin T
PubMed: 19342590
DOI: 10.1126/science.1164680 -
Current Opinion in Cell Biology Jun 2021The defining feature of the eukaryotic cell, the nucleus, is bounded by a double envelope. This envelope and the nuclear pores within it play a critical role in... (Review)
Review
The defining feature of the eukaryotic cell, the nucleus, is bounded by a double envelope. This envelope and the nuclear pores within it play a critical role in separating the genome from the cytoplasm. It also presents cells with a challenge. How are cells to remodel the nuclear compartment boundary during mitosis without compromising nuclear function? In the two billion years since the emergence of the first cells with a nucleus, eukaryotes have evolved a range of strategies to do this. At one extreme, the nucleus is disassembled upon entry into mitosis and then reassembled anew in the two daughter cells. At the other, cells maintain an intact nuclear compartment boundary throughout the division process. In this review, we discuss common features of the division process that underpin remodelling mechanisms, the topological challenges involved and speculate on the selective pressures that may drive the evolution of distinct modes of division.
Topics: Cell Nucleus; Cytoplasm; Humans; Mitosis; Nuclear Envelope; Nuclear Pore
PubMed: 33421755
DOI: 10.1016/j.ceb.2020.12.004 -
Nature Communications Nov 2021The mammalian SWI/SNF nucleosome remodeler is essential for spermatogenesis. Here, we identify a role for ARID2, a PBAF (Polybromo - Brg1 Associated Factor)-specific...
The mammalian SWI/SNF nucleosome remodeler is essential for spermatogenesis. Here, we identify a role for ARID2, a PBAF (Polybromo - Brg1 Associated Factor)-specific subunit, in meiotic division. Arid2 spermatocytes arrest at metaphase-I and are deficient in spindle assembly, kinetochore-associated Polo-like kinase1 (PLK1), and centromeric targeting of Histone H3 threonine3 phosphorylation (H3T3P) and Histone H2A threonine120 phosphorylation (H2AT120P). By determining ARID2 and BRG1 genomic associations, we show that PBAF localizes to centromeres and promoters of genes known to govern spindle assembly and nuclear division in spermatocytes. Consistent with gene ontology of target genes, we also identify a role for ARID2 in centrosome stability. Additionally, misexpression of genes such as Aurkc and Ppp1cc (Pp1γ), known to govern chromosome segregation, potentially compromises the function of the chromosome passenger complex (CPC) and deposition of H3T3P, respectively. Our data support a model where-in PBAF activates genes essential for meiotic cell division.
Topics: Animals; Cell Cycle Proteins; Centromere; Chromatin; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; Chromosome Segregation; DNA Helicases; Gene Silencing; Histones; Male; Mammals; Meiosis; Metaphase; Mice; Mice, Knockout; Nuclear Proteins; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Spermatocytes; Spermatogenesis; Transcription Factors; Transcriptome; Polo-Like Kinase 1
PubMed: 34772938
DOI: 10.1038/s41467-021-26828-1 -
Nature Communications Aug 2023Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in...
Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in therapeutical success. Functioning as HSP70's cochaperones, HSP40s determine the client specificity of HSP70s, and could be better targets for cancer therapy. Here we show that tumors defective in HSP40 member DNAJA2 are benefitted from immune-checkpoint blockade (ICB) therapy. Mechanistically, DNAJA2 maintains centrosome homeostasis by timely degrading key centriolar satellite proteins PCM1 and CEP290 via HSC70 chaperone-mediated autophagy (CMA). Tumor cells depleted of DNAJA2 or CMA factor LAMP2A exhibit elevated levels of centriolar satellite proteins, which causes aberrant mitosis characterized by abnormal spindles, chromosome missegregation and micronuclei formation. This activates the cGAS-STING pathway to enhance ICB therapy response in tumors derived from DNAJA2-deficient cells. Our study reveals a role for DNAJA2 to regulate mitotic division and chromosome stability and suggests DNAJA2 as a potential target to enhance cancer immunotherapy, thereby providing strategies to advance HSPs-based cancer therapy.
Topics: Humans; Mitosis; Cell Nucleus Division; Chromogranin A; Nucleotidyltransferases; Chromosomal Instability; HSP70 Heat-Shock Proteins; HSP40 Heat-Shock Proteins
PubMed: 37640708
DOI: 10.1038/s41467-023-40952-0 -
Current Opinion in Microbiology Dec 2015Within many fungal syncytia, nuclei behave independently despite sharing a common cytoplasm. Creation of independent nuclear zones of control in one cell is paradoxical... (Review)
Review
Within many fungal syncytia, nuclei behave independently despite sharing a common cytoplasm. Creation of independent nuclear zones of control in one cell is paradoxical considering random protein synthesis sites, predicted rapid diffusion rates, and well-mixed cytosol. In studying the surprising fungal nuclear autonomy, new principles of cellular organization are emerging. We discuss the current understanding of nuclear autonomy, focusing on asynchronous cell cycle progression where most work has been directed. Mechanisms underlying nuclear autonomy are diverse including mRNA localization, ploidy variability, and nuclear spacing control. With the challenges fungal syncytia face due to cytoplasmic size and shape, they serve as powerful models for uncovering new subcellular organization modes, variability sources among isogenic uninucleate cells, and the evolution of multicellularity.
Topics: Biological Evolution; Cell Nucleus; Cell Nucleus Division; Cytoplasm; Fungi
PubMed: 26379197
DOI: 10.1016/j.mib.2015.08.009 -
Nucleus (Austin, Tex.) Dec 2019Mitosis and meiosis in higher plants involve significant reconfiguration of the nuclear envelope and the proteins that interact with it. The dynamic series of events... (Review)
Review
Mitosis and meiosis in higher plants involve significant reconfiguration of the nuclear envelope and the proteins that interact with it. The dynamic series of events involves a range of interactions, movement, breakdown, and reformation of this complex system. Recently, progress has been made in identifying and characterizing the protein and membrane interactome that performs these complex tasks, including constituents of the nuclear envelope, the cytoskeleton, nucleoskeleton, and chromatin. This review will present the current understanding of these interactions and advances in knowledge of the processes for the breakdown and reformation of the nuclear envelope during cell divisions in plants.
Topics: Meiosis; Mitosis; Nuclear Envelope; Plant Cells
PubMed: 30879391
DOI: 10.1080/19491034.2019.1587277 -
Nucleus (Austin, Tex.) Dec 2022The kinetochore is a large proteinaceous structure assembled on the centromeres of chromosomes. The complex machinery links chromosomes to the mitotic spindle and is... (Review)
Review
The kinetochore is a large proteinaceous structure assembled on the centromeres of chromosomes. The complex machinery links chromosomes to the mitotic spindle and is essential for accurate chromosome segregation during cell division. The kinetochore is composed of two submodules: the inner and outer kinetochore. The inner kinetochore is assembled on centromeric chromatin and persists with centromeres throughout the cell cycle. The outer kinetochore attaches microtubules to the inner kinetochore, and assembles only during mitosis. The review focuses on recent advances in our understanding of the mechanisms governing the proper assembly of the outer kinetochore during mitosis and highlights open questions for future investigation.
Topics: Cell Cycle Checkpoints; Centromere; Chromosome Segregation; Kinetochores; Mitosis; Spindle Apparatus
PubMed: 36037227
DOI: 10.1080/19491034.2022.2115246 -
Trends in Cell Biology Dec 2021Nuclear pore complexes (NPCs) are huge protein assemblies within the nuclear envelope (NE) that serve as selective gates for macromolecular transport between nucleus and... (Review)
Review
Nuclear pore complexes (NPCs) are huge protein assemblies within the nuclear envelope (NE) that serve as selective gates for macromolecular transport between nucleus and cytoplasm. When higher eukaryotic cells prepare for division, they rapidly disintegrate NPCs during NE breakdown such that nuclear and cytoplasmic components mix to enable the formation of a cytoplasmic mitotic spindle. At the end of mitosis, reassembly of NPCs is coordinated with the establishment of the NE around decondensing chromatin. We review recent progress on mitotic NPC disassembly and reassembly, focusing on vertebrate cells. We highlight novel mechanistic insights into how NPCs are rapidly disintegrated into conveniently reusable building blocks, and put divergent models of (post-)mitotic NPC assembly into a spatial and temporal context.
Topics: Cell Nucleus; Humans; Mitosis; Nuclear Envelope; Nuclear Pore; Nuclear Pore Complex Proteins
PubMed: 34294532
DOI: 10.1016/j.tcb.2021.06.011 -
Cold Spring Harbor Perspectives in... Mar 2010The nuclear envelope (NE) is a highly regulated membrane barrier that separates the nucleus from the cytoplasm in eukaryotic cells. It contains a large number of... (Review)
Review
The nuclear envelope (NE) is a highly regulated membrane barrier that separates the nucleus from the cytoplasm in eukaryotic cells. It contains a large number of different proteins that have been implicated in chromatin organization and gene regulation. Although the nuclear membrane enables complex levels of gene expression, it also poses a challenge when it comes to cell division. To allow access of the mitotic spindle to chromatin, the nucleus of metazoans must completely disassemble during mitosis, generating the need to re-establish the nuclear compartment at the end of each cell division. Here, I summarize our current understanding of the dynamic remodeling of the NE during the cell cycle.
Topics: Animals; Cell Cycle; Cell Nucleus; Cell Proliferation; Chromatin; Cytoplasm; Humans; Mitosis; Models, Biological; Nuclear Envelope; Saccharomyces cerevisiae; Spindle Apparatus
PubMed: 20300205
DOI: 10.1101/cshperspect.a000539