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Cytokinesis-Based Constraints on Polarized Cell Growth in Fission Yeast  [PDF]
K. Adam Bohnert,Kathleen L. Gould
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1003004
Abstract: The rod-shaped fission yeast Schizosaccharomyces pombe, which undergoes cycles of monopolar-to-bipolar tip growth, is an attractive organism for studying cell-cycle regulation of polarity establishment. While previous research has described factors mediating this process from interphase cell tips, we found that division site signaling also impacts the re-establishment of bipolar cell growth in the ensuing cell cycle. Complete loss or targeted disruption of the non-essential cytokinesis protein Fic1 at the division site, but not at interphase cell tips, resulted in many cells failing to grow at new ends created by cell division. This appeared due to faulty disassembly and abnormal persistence of the cell division machinery at new ends of fic1Δ cells. Moreover, additional mutants defective in the final stages of cytokinesis exhibited analogous growth polarity defects, supporting that robust completion of cell division contributes to new end-growth competency. To test this model, we genetically manipulated S. pombe cells to undergo new end take-off immediately after cell division. Intriguingly, such cells elongated constitutively at new ends unless cytokinesis was perturbed. Thus, cell division imposes constraints that partially override positive controls on growth. We posit that such constraints facilitate invasive fungal growth, as cytokinesis mutants displaying bipolar growth defects formed numerous pseudohyphae. Collectively, these data highlight a role for previous cell cycles in defining a cell's capacity to polarize at specific sites, and they additionally provide insight into how a unicellular yeast can transition into a quasi-multicellular state.
Nuc2p, a Subunit of the Anaphase-Promoting Complex, Inhibits Septation Initiation Network Following Cytokinesis in Fission Yeast  [PDF]
Ting Gang Chew,Mohan K Balasubramanian
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.0040017
Abstract: In most cell types, mitosis and cytokinesis are tightly coupled such that cytokinesis occurs only once per cell cycle. The fission yeast Schizosaccharomyces pombe divides using an actomyosin-based contractile ring and is an attractive model for the study of the links between mitosis and cytokinesis. In fission yeast, the anaphase-promoting complex/cyclosome (APC/C) and the septation initiation network (SIN), a spindle pole body (SPB)–associated GTPase-driven signaling cascade, function sequentially to ensure proper coordination of mitosis and cytokinesis. Here, we find a novel interplay between the tetratricopeptide repeat (TPR) domain–containing subunit of the APC/C, Nuc2p, and the SIN, that appears to not involve other subunits of the APC/C. Overproduction of Nuc2p led to an increase in the presence of multinucleated cells, which correlated with a defect in actomyosin ring maintenance and localization of the SIN component protein kinases Cdc7p and Sid1p to the SPBs, indicative of defective SIN signaling. Conversely, loss of Nuc2p function led to increased SIN signaling, characterized by the persistent localization of Cdc7p and Sid1p on SPBs and assembly of multiple actomyosin rings and division septa. Nuc2p appears to function independently of the checkpoint with FHA and ring finger (CHFR)–related protein Dma1p, a known inhibitor of the SIN in fission yeast. Genetic and biochemical analyses established that Nuc2p might influence the nucleotide state of Spg1p GTPase, a key regulator of the SIN. We propose that Nuc2p, by inhibiting the SIN after cell division, prevents further deleterious cytokinetic events, thereby contributing to genome stability.
UCS Protein Rng3p Is Essential for Myosin-II Motor Activity during Cytokinesis in Fission Yeast  [PDF]
Benjamin C. Stark, Michael L. James, Luther W. Pollard, Vladimir Sirotkin, Matthew Lord
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079593
Abstract: UCS proteins have been proposed to operate as co-chaperones that work with Hsp90 in the de novo folding of myosin motors. The fission yeast UCS protein Rng3p is essential for actomyosin ring assembly and cytokinesis. Here we investigated the role of Rng3p in fission yeast myosin-II (Myo2p) motor activity. Myo2p isolated from an arrested rng3-65 mutant was capable of binding actin, yet lacked stability and activity based on its expression levels and inactivity in ATPase and actin filament gliding assays. Myo2p isolated from a myo2-E1 mutant (a mutant hyper-sensitive to perturbation of Rng3p function) showed similar behavior in the same assays and exhibited an altered motor conformation based on limited proteolysis experiments. We propose that Rng3p is not required for the folding of motors per se, but instead works to ensure the activity of intrinsically unstable myosin-II motors. Rng3p is specific to conventional myosin-II and the actomyosin ring, and is not required for unconventional myosin motor function at other actin structures. However, artificial destabilization of myosin-I motors at endocytic actin patches (using a myo1-E1 mutant) led to recruitment of Rng3p to patches. Thus, while Rng3p is specific to myosin-II, UCS proteins are adaptable and can respond to changes in the stability of other myosin motors.
Overexpression of the human MNB/DYRK1A gene induces formation of multinucleate cells through overduplication of the centrosome
Eishi Funakoshi, Takamitsu Hori, Tokuko Haraguchi, Yasushi Hiraoka, Jun Kudoh, Nobuyoshi Shimizu, Fumiaki Ito
BMC Cell Biology , 2003, DOI: 10.1186/1471-2121-4-12
Abstract: In this study, we examined HeLa cells transfected with cDNA encoding a green fluorescent protein (GFP)-MNB/DYRK1A fusion protein and found 2 patterns of expression: In one group of transfected cells, GFP-MNB/DYRK1A was localized as dots within the nucleus; and in the other group, it was overexpressed and had accumulated all over the nucleus. In the cells overexpressing GFP-MNB/DYRK1A, multinucleation was clearly observed; whereas in those with the nuclear dots, such aberrant nuclei were not found. Furthermore, in the latter cells, essential processes such as mitosis and cytokinesis occurred normally. Multinucleation was dependent on the kinase activity of MNB/DYRK1A, because it was not observed in cells overexpressing kinase activity-negative mutants, GFP-MNB/DYRK1A (K179R) and GFP-MNB/DYRK1A (Y310F/Y312F). Immunostaining of GFP-MNB/DYRK1A-overexpressing cells with specific antibodies against α- and γ-tubulin revealed that multiple copies of centrosomes and aberrant multipolar spindles were generated in these cells.These results indicate that overexpression of MNB/DYRK1A induces multinucleation in HeLa cells through overduplication of the centrosome during interphase and production of aberrant spindles and missegregation of chromosomes during mitosis.Down syndrome (trisomy 21) is the most frequent birth defect and is a major cause of mental retardation and congenital heart disease [1]. Besides the characteristic set of facial and physical features of individuals afflicted with it, this syndrome is associated with defects of the immune and endocrine systems, an increased rate of leukemia, and early onset of Alzheimer disease [1]. Although little is known about the mechanism by which trisomy 21 interferes with normal development, the increased dosage of the chromosomal elements clearly implies altered levels of gene expression as a causative factor.In most cases, patients with Down syndrome show trisomy of chromosome 21. Studies of cases with partial trisomy of chromo
A conserved histone deacetylase with a role in the regulation of cytokinesis in Schizosaccharomyces pombe
Charnpal Grewal, Jack Hickmott, Stefan Rentas, Jim Karagiannis
Cell Division , 2012, DOI: 10.1186/1747-1028-7-13
Abstract: In this report we identify the hos2 gene as the fission yeast HDAC3 ortholog. We show that Hos2p physically interacts with Set3p, Snt1p, and Hif2p, and that hos2? mutants are indeed compromised in their ability to reliably complete cell division in the presence of mild cytokinetic stresses. Furthermore, we demonstrate that over-expression of hos2 causes severe morphological and cytokinetic defects. Lastly, through recombinase mediated cassette exchange, we show that expression of human HDAC3 complements the cytokinetic defects exhibited by hos2? cells.These data support a model in which Hos2p functions as an essential component of the Set3p-Snt1p-Hif2p complex with respect to the regulation of cytokinesis. The ability of human HDAC3 to complement the cytokinesis defects associated with the deletion of the hos2 gene suggests that further analysis of this system could provide insight into the role of HDAC3 in both the regulation of cell division, as well as other biological processes influenced by HDAC3 deacetylation.In the fission yeast, Schizosaccharomyces pombe, regulatory mechanisms exist to ensure that cytokinesis takes place at the correct spatial location within the cell and at the proper temporal position of the cell cycle [1-5]. The proper spatial positioning of the cytokinetic actomyosin ring is controlled by the anilin-related protein, Mid1p, which - upon entry into mitosis - re-localizes from the nucleus to a medial band defining the future site of cell division [5-9]. The initiation of ring constriction, on the other hand, is signalled by a conserved regulatory module referred to as the Septation Initiation Network (SIN). The SIN is composed of a GTPase signalling cascade that is essential for the temporal co-ordination of cytokinesis, ring constriction, and for the deposition of the division septum [3,5,9,10].In addition to these mechanisms, recent work has also supported the existence of a cytokinesis monitoring system. This system has the capacity to g
The SET Domain Protein, Set3p, Promotes the Reliable Execution of Cytokinesis in Schizosaccharomyces pombe  [PDF]
Stefan Rentas, Reza Saberianfar, Charnpal Grewal, Rachelle Kanippayoor, Mithilesh Mishra, Dannel McCollum, Jim Karagiannis
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0031224
Abstract: In response to perturbation of the cell division machinery fission yeast cells activate regulatory networks that ensure the faithful completion of cytokinesis. For instance, when cells are treated with drugs that impede constriction of the actomyosin ring (low doses of Latrunculin A, for example) these networks ensure that cytokinesis is complete before progression into the subsequent mitosis. Here, we identify three previously uncharacterized genes, hif2, set3, and snt1, whose deletion results in hyper-sensitivity to LatA treatment and in increased rates of cytokinesis failure. Interestingly, these genes are orthologous to TBL1X, MLL5, and NCOR2, human genes that encode components of a histone deacetylase complex with a known role in cytokinesis. Through co-immunoprecipitation experiments, localization studies, and phenotypic analysis of gene deletion mutants, we provide evidence for an orthologous complex in fission yeast. Furthermore, in light of the putative role of the complex in chromatin modification, together with our results demonstrating an increase in Set3p levels upon Latrunculin A treatment, global gene expression profiles were generated. While this analysis demonstrated that the expression of cytokinesis genes was not significantly affected in set3Δ backgrounds, it did reveal defects in the ability of the mutant to regulate genes with roles in the cellular response to stress. Taken together, these findings support the existence of a conserved, multi-protein complex with a role in promoting the successful completion of cytokinesis.
Sporulation Genes Associated with Sporulation Efficiency in Natural Isolates of Yeast  [PDF]
Parul Tomar, Aatish Bhatia, Shweta Ramdas, Liyang Diao, Gyan Bhanot, Himanshu Sinha
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069765
Abstract: Yeast sporulation efficiency is a quantitative trait and is known to vary among experimental populations and natural isolates. Some studies have uncovered the genetic basis of this variation and have identified the role of sporulation genes (IME1, RME1) and sporulation-associated genes (FKH2, PMS1, RAS2, RSF1, SWS2), as well as non-sporulation pathway genes (MKT1, TAO3) in maintaining this variation. However, these studies have been done mostly in experimental populations. Sporulation is a response to nutrient deprivation. Unlike laboratory strains, natural isolates have likely undergone multiple selections for quick adaptation to varying nutrient conditions. As a result, sporulation efficiency in natural isolates may have different genetic factors contributing to phenotypic variation. Using Saccharomyces cerevisiae strains in the genetically and environmentally diverse SGRP collection, we have identified genetic loci associated with sporulation efficiency variation in a set of sporulation and sporulation-associated genes. Using two independent methods for association mapping and correcting for population structure biases, our analysis identified two linked clusters containing 4 non-synonymous mutations in genes – HOS4, MCK1, SET3, and SPO74. Five regulatory polymorphisms in five genes such as MLS1 and CDC10 were also identified as putative candidates. Our results provide candidate genes contributing to phenotypic variation in the sporulation efficiency of natural isolates of yeast.
Key players in yeast sporulation  [cached]
Rachel Brem
Genome Biology , 2001, DOI: 10.1186/gb-2001-2-2-reports0003
Abstract: Primig et al. made use of W303 and SK1, two strains of budding yeast with different sporulation efficiencies. The authors measured mRNA levels of all genes in W303 and SK1, at one- or two-hour timepoints throughout sporulation. The authors looked for genes whose expression levels fluctuated during sporulation by at least 4-fold in SK1 and at least 2.5-fold in W303. The 915 genes that meet these empirical criteria are called by Primig et al. 'core meiotic genes'. They are candidates for general players in meiosis, as elements controlling strain-specific meiotic behaviors are weeded out by the selection method. As a control, Primig et al. measured expression changes of all genes over time in starved, non-sporulating variants of W303 and SK1. Of the 915 core genes, an unreported fraction appear regulated in one control, and 5% appear regulated in both controls.Clustering analysis was performed on mRNA expression data of all SK1 genes whose expression fluctuated during sporulation. The result of this calculation was a set of clusters of genes. All the genes within each cluster have similar expression patterns over time. The SK1 clusters can be empirically rationalized on the basis of known protein functions. But are they general across yeast strains? Primig et al. addressed this question indirectly by making a graph for each of the 915 core genes which plots mRNA levels over time from the isotype in SK1 against those from the isotype in W303. The correlation coefficient of 60% of these graphs is over 0.8. Thus, only 60% of core genes follow the same temporal pattern in the two yeast strains. This implies that the clustering from the SK1 strain is generally useful for only 60% of core genes.Data from this study is available at Rochelle E. Esposito's lab and the Meiosis database.Primig et al. conclude that a fraction of their 915 core genes are likely to be key players in meiosis, and that their cluster designations may spur new models of regulation in meiosis.The strengt
Benchmarking Nuclear Fission Theory  [PDF]
G. F. Bertsch,W. Loveland,W. Nazarewicz,P. Talou
Physics , 2015, DOI: 10.1088/0954-3899/42/7/077001
Abstract: We suggest a small set of fission observables to be used as test cases for validation of theoretical calculations. The purpose is to provide common data to facilitate the comparison of different fission theories and models. The proposed observables are chosen from fission barriers, spontaneous fission lifetimes, fission yield characteristics, and fission isomer excitation energies.
Tumor Suppressor DYRK1A Effects on Proliferation and Chemoresistance of AML Cells by Downregulating c-Myc  [PDF]
Qiang Liu, Na Liu, Shaolei Zang, Heng Liu, Pin Wang, Chunyan Ji, Xiulian Sun
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098853
Abstract: Acute myeloid leukemia (AML), caused by abnormal proliferation and accumulation of hematopoietic progenitor cells, is one of the most common malignancies in adults. We reported here DYRK1A expression level was reduced in the bone marrow of adult AML patients, comparing to normal controls. Overexpression of DYRK1A inhibited the proliferation of AML cell lines by increasing the proportion of cells undergoing G0/G1 phase. We reasoned that the proliferative inhibition was due to downregulation of c-Myc by DYRK1A, through mediating its degradation. Moreover, overexpression of c-Myc markedly reversed AML cell growth inhibition induced by DYRK1A. DYRK1A also had significantly lower expression in relapsed/refractory AML patients, comparing to newly-diagnosed AML patients, which indicated the role of DYRK1A in chemoresistance of AML. Our study provided functional evidences for DYRK1A as a potential tumor suppressor in AML.
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