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Annual Review of Genetics Nov 2023The raison d'être of meiosis is shuffling of genetic information via Mendelian segregation and, within individual chromosomes, by DNA crossing-over. These outcomes are... (Review)
Review
The raison d'être of meiosis is shuffling of genetic information via Mendelian segregation and, within individual chromosomes, by DNA crossing-over. These outcomes are enabled by a complex cellular program in which interactions between homologous chromosomes play a central role. We first provide a background regarding the basic principles of this program. We then summarize the current understanding of the DNA events of recombination and of three processes that involve whole chromosomes: homolog pairing, crossover interference, and chiasma maturation. All of these processes are implemented by direct physical interaction of recombination complexes with underlying chromosome structures. Finally, we present convergent lines of evidence that the meiotic program may have evolved by coupling of this interaction to late-stage mitotic chromosome morphogenesis.
Topics: Chromosome Pairing; Meiosis; Chromosomes; DNA; Chromosome Segregation; Crossing Over, Genetic
PubMed: 37788458
DOI: 10.1146/annurev-genet-061323-044915 -
Science (New York, N.Y.) Aug 2023Nonhomologous end-joining (NHEJ) and homologous recombination (HR) are the primary pathways for repairing DNA double-strand breaks (DSBs) during interphase, whereas...
Nonhomologous end-joining (NHEJ) and homologous recombination (HR) are the primary pathways for repairing DNA double-strand breaks (DSBs) during interphase, whereas microhomology-mediated end-joining (MMEJ) has been regarded as a backup mechanism. Through CRISPR-Cas9-based synthetic lethal screens in cancer cells, we identified subunits of the 9-1-1 complex (RAD9A-RAD1-HUS1) and its interacting partner, RHINO, as crucial MMEJ factors. We uncovered an unexpected function for RHINO in restricting MMEJ to mitosis. RHINO accumulates in M phase, undergoes Polo-like kinase 1 (PLK1) phosphorylation, and interacts with polymerase θ (Polθ), enabling its recruitment to DSBs for subsequent repair. Additionally, we provide evidence that MMEJ activity in mitosis repairs persistent DSBs that originate in S phase. Our findings offer insights into the synthetic lethal relationship between the genes and and and the synergistic effect of Polθ and poly(ADP-ribose) polymerase (PARP) inhibitors.
Topics: Humans; Cell Cycle Proteins; DNA Breaks, Double-Stranded; DNA End-Joining Repair; Exonucleases; HEK293 Cells; Mitosis; Poly(ADP-ribose) Polymerases
PubMed: 37440612
DOI: 10.1126/science.adh3694 -
Nature Jul 2023In mammalian cells, the decision to proliferate is thought to be irreversibly made at the restriction point of the cell cycle, when mitogen signalling engages a positive...
In mammalian cells, the decision to proliferate is thought to be irreversibly made at the restriction point of the cell cycle, when mitogen signalling engages a positive feedback loop between cyclin A2/cyclin-dependent kinase 2 (CDK2) and the retinoblastoma protein. Contrary to this textbook model, here we show that the decision to proliferate is actually fully reversible. Instead, we find that all cycling cells will exit the cell cycle in the absence of mitogens unless they make it to mitosis and divide first. This temporal competition between two fates, mitosis and cell cycle exit, arises because cyclin A2/CDK2 activity depends upon CDK4/6 activity throughout the cell cycle, not just in G1 phase. Without mitogens, mitosis is only observed when the half-life of cyclin A2 protein is long enough to sustain CDK2 activity throughout G2/M. Thus, cells are dependent on mitogens and CDK4/6 activity to maintain CDK2 activity and retinoblastoma protein phosphorylation throughout interphase. Consequently, even a 2-h delay in a cell's progression towards mitosis can induce cell cycle exit if mitogen signalling is lost. Our results uncover the molecular mechanism underlying the restriction point phenomenon, reveal an unexpected role for CDK4/6 activity in S and G2 phases and explain the behaviour of all cells following loss of mitogen signalling.
Topics: Animals; Cell Cycle; Cyclin A2; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; G2 Phase; Mitogens; Mitosis; Phosphorylation; Retinoblastoma Protein; Cyclin-Dependent Kinase 6; S Phase; G1 Phase
PubMed: 37407814
DOI: 10.1038/s41586-023-06274-3 -
Nature Jul 2023Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers, but whether they are mechanistically linked is unknown....
Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei and subsequent rupture of the micronuclear envelope profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.
Topics: Animals; Humans; Mice; Chromatin; Chromosomal Instability; Chromosomes; Epigenesis, Genetic; Histones; Neoplasms; Micronuclei, Chromosome-Defective; Chromosome Segregation; Mitosis; DNA Copy Number Variations; Protein Processing, Post-Translational
PubMed: 37286593
DOI: 10.1038/s41586-023-06084-7 -
Science Advances Sep 2023EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand and mechanical inputs can activate EGFR-ERK signaling,...
EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand and mechanical inputs can activate EGFR-ERK signaling, the molecules linking mechanical force to this axis have remained mysterious. We previously found that stretch promotes mitosis via the stretch-activated ion channel Piezo1 and ERK signaling. Here, we show that Piezo1 provides the missing link between mechanical signals and EGFR-ERK activation. While both EGF- and Piezo1-dependent activation trigger clathrin-mediated EGFR endocytosis and ERK activation, EGF relies on canonical tyrosine autophosphorylation, whereas Piezo1 involves Src-p38 kinase-dependent serine phosphorylation. In addition, unlike EGF, ex vivo lung slices treated with Piezo1 agonist promoted cell cycle re-entry via nuclear ERK, AP-1 (FOS and JUN), and YAP accumulation, typical of regenerative and malignant signaling. Our results suggest that mechanical activation via Piezo1, Src, and p38 may be more relevant to controlling repair, regeneration, and cancer growth than tyrosine kinase signaling via canonical EGF signaling, suggesting an alternative therapeutic approach.
Topics: Epidermal Growth Factor; Signal Transduction; src-Family Kinases; Endocytosis; Mitosis; ErbB Receptors
PubMed: 37756411
DOI: 10.1126/sciadv.adi1328 -
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 -
Current Opinion in Structural Biology Aug 2023Chromosomes transform during the cell cycle, allowing transcription and replication during interphase and chromosome segregation during mitosis. Morphological changes... (Review)
Review
Chromosomes transform during the cell cycle, allowing transcription and replication during interphase and chromosome segregation during mitosis. Morphological changes are thought to be driven by the combined effects of DNA loop extrusion and a chromatin solubility phase transition. By extruding the chromatin fibre into loops, condensins enrich at an axial core and provide resistance to spindle pulling forces. Mitotic chromosomes are further compacted by deacetylation of histone tails, rendering chromatin insoluble and resistant to penetration by microtubules. Regulation of surface properties by Ki-67 allows independent chromosome movement in early mitosis and clustering during mitotic exit. Recent progress has provided insight into how the extraordinary material properties of chromatin emerge from these activities, and how these properties facilitate faithful chromosome segregation.
Topics: Chromosomes; Chromatin; Mitosis; Histones; Chromosome Segregation
PubMed: 37279615
DOI: 10.1016/j.sbi.2023.102617