scholarly journals Intertwined Functions of Separase and Caspase in Cell Division and Programmed Cell Death

2019 ◽  
Author(s):  
Pan-Young Jeong ◽  
Ashish Kumar ◽  
Pradeep Joshi ◽  
Joel H. Rothman
Keyword(s):  
Cell Proliferation ◽  
Cell Division ◽  
Chromosome Segregation ◽  
Meiotic Chromosome ◽  
Cysteine Proteases ◽  
Embryonic Lethality ◽  
Substrate Specificities ◽  
C Elegans ◽  
Cell Suicide ◽  
Chromosome Disjunction

AbstractTimely sister chromatid separation, promoted by separase, is essential for faithful chromosome segregation. Separase is a member of the CD clan of cysteine proteases, which also includes the pro-apoptotic enzymes known as caspases. We report that the C. elegans separase SEP-1, primarily known for its role in cell division, is required for apoptosis when the predominant pro-apoptotic caspase CED-3 is compromised. Loss of SEP-1 results in extra surviving cells in a weak ced-3(−) mutant, and suppresses the embryonic lethality of a mutant defective for the apoptotic suppressor ced-9/Bcl-2. We also report apparent non-apoptotic roles for CED-3 in promoting germ cell proliferation and germline meiotic chromosome disjunction and the normal rate of embryonic development. Moreover, loss of the soma-specific (CSP-3) and germline-specific (CSP-2) caspase inhibitors results in CED-3-dependent suppression of embryonic lethality and meiotic chromosome non-disjunction respectively, when separase function is compromised. Thus, while caspases and separases have evolved different substrate specificities associated with their specialized functions in apoptosis and cell division respectively, they appear to have retained the residual ability to participate in both processes, supporting the view that co-option of components in cell division may have led to the innovation of programmed cell suicide early in metazoan evolution.

scholarly journals Mitotic chromosome condensation requires phosphorylation of the centromeric protein KNL-2 in C. elegans

2021 ◽  
Author(s):  
Joanna M Wenda ◽  
Reinier F Prosée ◽  
Caroline Gabus ◽  
Florian A Steiner
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Chromosome ◽  
Chromosome Condensation ◽  
Embryonic Lethality ◽  
Phosphorylation Sites ◽  
C Elegans ◽  
Microtubule Attachment ◽  
Centromeric Protein ◽  
Mitotic Chromosome Condensation

Centromeres are chromosomal regions that serve as sites for kinetochore formation and microtubule attachment, processes that are essential for chromosome segregation during mitosis. Centromeres are almost universally defined by the histone variant CENP-A. In the holocentric nematode C. elegans, CENP-A deposition depends on the loading factor KNL-2. Depletion of either CENP-A or KNL-2 results in defects in centromere maintenance, chromosome condensation and kinetochore formation, leading to chromosome segregation failure. Here, we show that KNL-2 is phosphorylated by CDK-1, and that mutation of three C-terminal phosphorylation sites causes chromosome segregation defects and an increase in embryonic lethality. In strains expressing phosphodeficient KNL-2, CENP-A and kinetochore proteins are properly localised, indicating that the role of KNL-2 in centromere maintenance is not affected. Instead, the mutant embryos exhibit reduced mitotic levels of condensin II on chromosomes and significant chromosome condensation impairment. Our findings separate the functions of KNL-2 in CENP-A loading and chromosome condensation and demonstrate that KNL-2 phosphorylation regulates the cooperation between centromeric regions and the condensation machinery in C. elegans.

scholarly journals The MAP kinase pathway coordinates crossover designation with disassembly of synaptonemal complex proteins during meiosis

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Saravanapriah Nadarajan ◽  
Firaz Mohideen ◽  
Yonatan B Tzur ◽  
Nuria Ferrandiz ◽  
Oliver Crawley ◽  
...  
Keyword(s):  
Map Kinase ◽  
Synaptonemal Complex ◽  
Chromosome Segregation ◽  
Meiotic Chromosome ◽  
Late Pachytene ◽  
C Elegans ◽  
Map Kinase Pathway ◽  
Rho Gef ◽  
Kinase Signaling Pathway ◽  
Kinase Pathway

Asymmetric disassembly of the synaptonemal complex (SC) is crucial for proper meiotic chromosome segregation. However, the signaling mechanisms that directly regulate this process are poorly understood. Here we show that the mammalian Rho GEF homolog, ECT-2, functions through the conserved RAS/ERK MAP kinase signaling pathway in the C. elegans germline to regulate the disassembly of SC proteins. We find that SYP-2, a SC central region component, is a potential target for MPK-1-mediated phosphorylation and that constitutively phosphorylated SYP-2 impairs the disassembly of SC proteins from chromosomal domains referred to as the long arms of the bivalents. Inactivation of MAP kinase at late pachytene is critical for timely disassembly of the SC proteins from the long arms, and is dependent on the crossover (CO) promoting factors ZHP-3/RNF212/Zip3 and COSA-1/CNTD1. We propose that the conserved MAP kinase pathway coordinates CO designation with the disassembly of SC proteins to ensure accurate chromosome segregation.

scholarly journals Shake It Off: The Elimination of Erroneous Kinetochore-Microtubule Attachments and Chromosome Oscillation

2021 ◽  
Vol 22 (6) ◽  
pp. 3174
Author(s):  
Ayumu Yamamoto
Keyword(s):  
Cell Proliferation ◽  
Sexual Reproduction ◽  
Fission Yeast ◽  
Chromosome Segregation ◽  
Meiotic Chromosome ◽  
Spindle Poles ◽  
Selective Elimination ◽  
Random Nature ◽  
Attachment Process ◽  
Segregation Of Chromosomes

Cell proliferation and sexual reproduction require the faithful segregation of chromosomes. Chromosome segregation is driven by the interaction of chromosomes with the spindle, and the attachment of chromosomes to the proper spindle poles is essential. Initial attachments are frequently erroneous due to the random nature of the attachment process; however, erroneous attachments are selectively eliminated. Proper attachment generates greater tension at the kinetochore than erroneous attachments, and it is thought that attachment selection is dependent on this tension. However, studies of meiotic chromosome segregation suggest that attachment elimination cannot be solely attributed to tension, and the precise mechanism of selective elimination of erroneous attachments remains unclear. During attachment elimination, chromosomes oscillate between the spindle poles. A recent study on meiotic chromosome segregation in fission yeast has suggested that attachment elimination is coupled to chromosome oscillation. In this review, the possible contribution of chromosome oscillation in the elimination of erroneous attachment is discussed in light of the recent finding.

scholarly journals Synaptonemal complex components are required for meiotic checkpoint function in C. elegans

2016 ◽  
Author(s):  
Tisha Bohr ◽  
Guinevere Ashley ◽  
Evan Eggleston ◽  
Kyra Firestone ◽  
Needhi Bhalla
Keyword(s):  
Synaptonemal Complex ◽  
Chromosome Segregation ◽  
Meiotic Chromosome ◽  
Checkpoint Response ◽  
Homologous Chromosomes ◽  
C Elegans ◽  
Homolog Pairing ◽  
The Stability ◽  
Complex Components

AbstractSynapsis involves the assembly of a proteinaceous structure, the synaptonemal complex (SC), between paired homologous chromosomes and is essential for proper meiotic chromosome segregation. In C. elegans, the synapsis checkpoint selectively removes nuclei with unsynapsed chromosomes by inducing apoptosis. This checkpoint depends on Pairing Centers (PCs), cis-acting sites that promote pairing and synapsis. We have hypothesized that the stability of homolog pairing at PCs is monitored by this checkpoint. Here, we report that SC components SYP-3, HTP-3, HIM-3 and HTP-1 are required for a functional synapsis checkpoint. Mutation of these components does not abolish PC function, demonstrating they are bonafide checkpoint components. Further, we identify mutant backgrounds in which the instability of homolog pairing at PCs does not correlate with the synapsis checkpoint response. Altogether, these data suggest that, in addition to homolog pairing, SC assembly may be monitored by the synapsis checkpoint.

scholarly journals Spatial and temporal control of targeting Polo-like kinase during meiotic prophase

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
James N. Brandt ◽  
Katarzyna A. Hussey ◽  
Yumi Kim
Keyword(s):  
Chromosome Segregation ◽  
Meiotic Prophase ◽  
Meiotic Chromosome ◽  
Holocentric Chromosomes ◽  
Cyclin Dependent Kinase ◽  
Chromosome Dynamics ◽  
C Elegans ◽  
Meiotic Progression ◽  
Crossover Site ◽  
Meiosis I

Polo-like kinases (PLKs) play widely conserved roles in orchestrating meiotic chromosome dynamics. However, how PLKs are targeted to distinct subcellular localizations during meiotic progression remains poorly understood. Here, we demonstrate that the cyclin-dependent kinase CDK-1 primes the recruitment of PLK-2 to the synaptonemal complex (SC) through phosphorylation of SYP-1 in C. elegans. SYP-1 phosphorylation by CDK-1 occurs just before meiotic onset. However, PLK-2 docking to the SC is prevented by the nucleoplasmic HAL-2/3 complex until crossover designation, which constrains PLK-2 to special chromosomal regions known as pairing centers to ensure proper homologue pairing and synapsis. PLK-2 is targeted to crossover sites primed by CDK-1 and spreads along the SC by reinforcing SYP-1 phosphorylation on one side of each crossover only when threshold levels of crossovers are generated. Thus, the integration of chromosome-autonomous signaling and a nucleus-wide crossover-counting mechanism partitions holocentric chromosomes relative to the crossover site, which ultimately defines the pattern of chromosome segregation during meiosis I.

scholarly journals Chromosome segregation during female meiosis in C. elegans: A tale of pushing and pulling

2020 ◽  
Vol 219 (12) ◽  
Author(s):  
Samuel J.P. Taylor ◽  
Federico Pelisch
Keyword(s):  
Chromosome Segregation ◽  
Meiotic Chromosome ◽  
Female Meiosis ◽  
C Elegans ◽  
Early Stages ◽  
Pushing And Pulling

The role of the kinetochore during meiotic chromosome segregation in C. elegans oocytes has been a matter of controversy. Danlasky et al. (2020. J. Cell. Biol.https://doi.org/10.1083/jcb.202005179) show that kinetochore proteins KNL-1 and KNL-3 are required for early stages of anaphase during female meiosis, suggesting a new kinetochore-based model of chromosome segregation.

scholarly journals Dynein-dynactin segregate meiotic chromosomes in C. elegans spermatocytes

2020 ◽  
Author(s):  
Daniel J. Barbosa ◽  
Vanessa Teixeira ◽  
Joana Duro ◽  
Ana X. Carvalho ◽  
Reto Gassmann
Keyword(s):  
Chromosome Segregation ◽  
Protein Misfolding ◽  
Meiotic Chromosome ◽  
Spindle Assembly ◽  
Cell Types ◽  
Early Embryo ◽  
Loss Of Function ◽  
C Elegans ◽  
Spindle Elongation

ABSTRACTThe dynactin complex is an essential co-factor of the microtubule-based motor dynein. Dynein-dynactin have well-documented roles in spindle assembly and positioning during C. elegans female meiosis and embryonic mitosis, while dynein-dynactin’s contribution to male meiosis has not been investigated. Here, we characterize the G33S mutation in DNC-1’s N-terminal microtubule binding domain, which corresponds to G59S in the human dynactin subunit p150/Glued that causes motor neuron disease. In spermatocytes, dnc-1(G33S) delays spindle assembly and penetrantly inhibits anaphase spindle elongation in meiosis I, which prevents homologous chromosome segregation and generates aneuploid sperm with an extra centrosome. Consequently, embryos produced by dnc-1(G33S) hermaphrodites exhibit a high incidence of tetrapolar mitotic spindles, yet dnc-1(G33S) embryos with bipolar spindles proceed through early mitotic divisions without errors in chromosome segregation. Deletion of the DNC-1 N-terminus shows that defective meiosis in dnc-1(G33S) spermatocytes is not due to DNC-1’s inability to interact with microtubules. Rather, our results suggest that the DNC-1(G33S) protein, which is aggregation-prone in vitro, is less stable in spermatocytes than the early embryo, resulting in different phenotypic severity in the two dividing tissues. Thus, the unusual hypomorphic nature of the dnc-1(G33S) mutant reveals that dynein-dynactin drive meiotic chromosome segregation in spermatocytes and illustrates that the extent to which protein misfolding leads to loss of function can vary significantly between cell types.

scholarly journals Excess crossovers impede faithful meiotic chromosome segregation in C. elegans

2020 ◽  
Author(s):  
Jeremy A. Hollis ◽  
Marissa L. Glover ◽  
Aleesa Schlientz ◽  
Cori K. Cahoon ◽  
Bruce Bowerman ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Chromosome Segregation ◽  
High Frequency ◽  
Meiotic Chromosome ◽  
Dependent Manner ◽  
Homologous Chromosomes ◽  
Crossover Interference ◽  
C Elegans ◽  
Functional Consequences ◽  
Chromosome Bridges

AbstractDuring meiosis, at least one crossover must form between each pair of homologous chromosomes to ensure their proper partitioning. However, most organisms limit the number of crossovers by a phenomenon called crossover interference; why this occurs is not well understood. Here we investigate the functional consequences of extra crossovers in Caenorhabditis elegans. Using a fusion chromosome that exhibits a high frequency of supernumerary crossovers, we find that essential chromosomal structures are mispatterned, subjecting chromosomes to improper spindle forces and leading to congression and segregation defects. Moreover, we uncover mechanisms that counteract these errors; anaphase I chromosome bridges were often able to resolve in a LEM-3 nuclease dependent manner, and tethers between homologs that persisted were frequently resolved during Meiosis II by a second mechanism. This study thus provides evidence that excess crossovers impact chromosome patterning and segregation, and also sheds light on how these errors are corrected.

scholarly journals Molecular basis for PICS-mediated piRNA biogenesis and cell division

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiaoyang Wang ◽  
Chenming Zeng ◽  
Shanhui Liao ◽  
Zhongliang Zhu ◽  
Jiahai Zhang ◽  
...  
Keyword(s):  
Cell Division ◽  
Chromosome Segregation ◽  
Cell Biology ◽  
Interaction Network ◽  
C Elegans ◽  
Biochemical Experiment ◽  
In Vitro Interaction ◽  
Structural Insights

AbstractBy incorporating two mutually exclusive factors, PID-1 and TOST-1, C. elegans PICS complex plays important roles in piRNA biogenesis, chromosome segregation and cell division. We firstly map the interaction network between PICS subunits, then uncover the mechanisms underlying the interactions between PICS subunits by solving several complex structures, including those of TOFU-6/PICS-1, ERH-2/PICS-1, and ERH-2/TOST-1. Our biochemical experiment also demonstrates that PICS exists as an octamer consisting of two copies of each subunit. Combining structural analyses with mutagenesis experiments, we identify interfacial residues of PICS subunits that are critical for maintaining intact PICS complex in vitro. Furthermore, using genetics, cell biology and imaging experiments, we find that those mutants impairing the in vitro interaction network within PICS, also lead to dysfunction of PICS in vivo, including mislocalization of PICS, and reduced levels of piRNAs or aberrant chromosome segregation and cell division. Therefore, our work provides structural insights into understanding the PICS-mediated piRNA biogenesis and cell division.

scholarly journals The conserved phosphatase GSP-2/PP1 promotes germline immortality via small RNA-mediated genome silencing during meiosis

2018 ◽  
Author(s):  
Katherine Kretovich Billmyre ◽  
Anna-lisa Doebley ◽  
Bree Heestand ◽  
Tony Belicard ◽  
Aya Sato-Carlton ◽  
...  
Keyword(s):  
Germ Cell ◽  
Chromosome Segregation ◽  
Small Rna ◽  
Protein Phosphatase ◽  
Germ Line ◽  
Meiotic Chromosome ◽  
Loss Of Function ◽  
Homologous Chromosomes ◽  
C Elegans ◽  
Cell Immortality

AbstractGenomic silencing can promote germ cell immortality, or transgenerational maintenance of the germ line, via mechanisms that may occur during mitosis or meiosis. Here we report that the gsp-2 PP1/Glc7 phosphatase promotes germ cell immortality. We identified a separation-of-function allele of C. elegans GSP-2 that caused a meiosis-specific chromosome segregation defect and defects in transgenerational small RNA-induced genome silencing. GSP-2 is recruited to meiotic chromosomes by LAB-1, which also promoted germ cell immortality. Sterile gsp-2 and lab-1 mutant adults displayed germline degeneration, univalents and histone phosphorylation defects in oocytes, similar to small RNA genome silencing mutants. Epistasis and RNA analysis suggested that GSP-2 functions downstream of small RNAs. We conclude that a meiosis-specific function of GSP-2/LAB-1 ties small RNA-mediated silencing of the epigenome to germ cell immortality. Given that hemizygous genetic elements can drive transgenerational epigenomic silencing, and given that LAB-1 promotes pairing of homologous chromosomes and localizes to the interface between homologous chromosomes during pachytene, we suggest that discontinuities at this interface could promote nuclear silencing in a manner that depends on GSP-2.Author SummaryThe germ line of an organism is considered immortal in its capacity to give rise to an unlimited number of future generations. To protect the integrity of the germ line, mechanisms act to suppress the accumulation of transgenerational damage to the genome or epigenome. Loss of germ cell immortality can result from mutations that disrupt the small RNA-mediated silencing pathway that helps to protect the integrity of the epigenome. Here we report for the first time that the C. elegans protein phosphatase GSP-2 that promotes core chromosome biology functions during meiosis is also required for germ cell immortality. Specifically, we identified a partial loss of function allele of gsp-2 that exhibits defects in meiotic chromosome segregation and is also dysfunctional for transgenerational small RNA-mediated genome silencing. Our results are consistent with a known role of Drosophila Protein Phosphatase 1 in heterochromatin silencing, and point to a meiotic phosphatase function that is relevant to germ cell immortality, conceivably related to its roles in chromosome pairing or sister chromatid cohesion.

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