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Spatiotemporal regulation of the Dma1-mediated mitotic checkpoint coordinates mitosis with cytokinesis.
Cullati SN, Gould KL
(2019) Curr Genet 65: 663-668
MeSH Terms: Cell Cycle Checkpoints, Cell Cycle Proteins, Cytokinesis, Mitosis, Phosphorylation, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Spatio-Temporal Analysis, Ubiquitination
Show Abstract · Added April 10, 2019
During cell division, the timing of mitosis and cytokinesis must be ordered to ensure that each daughter cell receives a complete, undamaged copy of the genome. In fission yeast, the septation initiation network (SIN) is responsible for this coordination, and a mitotic checkpoint dependent on the E3 ubiquitin ligase Dma1 and the protein kinase CK1 controls SIN signaling to delay cytokinesis when there are errors in mitosis. The participation of kinases and ubiquitin ligases in cell cycle checkpoints that maintain genome integrity is conserved from yeast to human, making fission yeast an excellent model system in which to study checkpoint mechanisms. In this review, we highlight recent advances and remaining questions related to checkpoint regulation, which requires the synchronized modulation of protein ubiquitination, phosphorylation, and subcellular localization.
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9 MeSH Terms
Cdk1-dependent phosphoinhibition of a formin-F-BAR interaction opposes cytokinetic contractile ring formation.
Willet AH, Bohnert KA, Gould KL
(2018) Mol Biol Cell 29: 713-721
MeSH Terms: Actin Cytoskeleton, Actins, CDC2 Protein Kinase, Cell Cycle Proteins, Cell Division, Cytokinesis, Cytoskeletal Proteins, GTP-Binding Proteins, Phosphorylation, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 14, 2018
In , cytokinesis requires the assembly and constriction of an actomyosin-based contractile ring (CR). A single essential formin, Cdc12, localizes to the cell middle upon mitotic onset and nucleates the F-actin of the CR. Cdc12 medial recruitment is mediated in part by its direct binding to the F-BAR scaffold Cdc15. Given that Cdc12 is hyperphosphorylated in M phase, we explored whether Cdc12 phosphoregulation impacts its association with Cdc15 during mitosis. We found that Cdk1, a major mitotic kinase, phosphorylates Cdc12 on six N-terminal residues near the Cdc15-binding site, and phosphorylation on these sites inhibits its interaction with the Cdc15 F-BAR domain. Consistent with this finding, a mutant with all six Cdk1 sites changed to phosphomimetic residues () displays phenotypes similar to , in which the Cdc15-binding motif is disrupted; both show reduced Cdc12 at the CR and delayed CR formation. Together, these results indicate that Cdk1 phosphorylation of formin Cdc12 antagonizes its interaction with Cdc15 and thereby opposes Cdc12's CR localization. These results are consistent with a general role for Cdk1 in inhibiting cytokinesis until chromosome segregation is complete.
© 2018 Willet et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).
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11 MeSH Terms
Nanoscale architecture of the contractile ring.
McDonald NA, Lind AL, Smith SE, Li R, Gould KL
(2017) Elife 6:
MeSH Terms: Cell Cycle Proteins, Cell Division, Cell Membrane, Cytoplasm, Fluorescence Resonance Energy Transfer, Macromolecular Substances, Microscopy, Fluorescence, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 14, 2018
The contractile ring is a complex molecular apparatus which physically divides many eukaryotic cells. Despite knowledge of its protein composition, the molecular architecture of the ring is not known. Here we have applied super-resolution microscopy and FRET to determine the nanoscale spatial organization of contractile ring components relative to the plasma membrane. Similar to other membrane-tethered actin structures, we find proteins localize in specific layers relative to the membrane. The most membrane-proximal layer (0-80 nm) is composed of membrane-binding scaffolds, formin, and the tail of the essential myosin-II. An intermediate layer (80-160 nm) consists of a network of cytokinesis accessory proteins as well as multiple signaling components which influence cell division. Farthest from the membrane (160-350 nm) we find F-actin, the motor domains of myosins, and a major F-actin crosslinker. Circumferentially within the ring, multiple proteins proximal to the membrane form clusters of different sizes, while components farther from the membrane are uniformly distributed. This comprehensive organizational map provides a framework for understanding contractile ring function.
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9 MeSH Terms
Phosphoinositide-mediated ring anchoring resists perpendicular forces to promote medial cytokinesis.
Snider CE, Willet AH, Chen JS, Arpağ G, Zanic M, Gould KL
(2017) J Cell Biol 216: 3041-3050
MeSH Terms: 1-Phosphatidylinositol 4-Kinase, Cell Cycle Proteins, Cytokinesis, GTP-Binding Proteins, Glycosylphosphatidylinositols, Myosin Type V, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added March 14, 2018
Many eukaryotic cells divide by assembling and constricting an actin- and myosin-based contractile ring (CR) that is physically linked to the plasma membrane (PM). In this study, we report that cells lacking , which encodes a conserved PM scaffold for the phosphatidylinositol-4 kinase Stt4, build CRs that can slide away from the cell middle during anaphase in a myosin V-dependent manner. The Efr3-dependent CR-anchoring mechanism is distinct from previously reported pathways dependent on the Fes/CIP4 homology Bin-Amphiphysin-Rvs167 (F-BAR) protein Cdc15 and paxillin Pxl1. In , the concentrations of several membrane-binding proteins were reduced in the CR and/or on the PM. Our results suggest that proper PM lipid composition is important to stabilize the central position of the CR and resist myosin V-based forces to promote the fidelity of cell division.
© 2017 Snider et al.
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8 MeSH Terms
The gene family that cheats Mendel.
Shropshire JD, Rokas A
(2017) Elife 6:
MeSH Terms: Alleles, Meiosis, Poisons, Schizosaccharomyces, Spores, Fungal
Show Abstract · Added March 21, 2018
Some alleles of the gene family can increase their chances of spreading by using poisons to kill other alleles, and antidotes to save themselves.
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5 MeSH Terms
Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity.
McDonald KR, Guise AJ, Pourbozorgi-Langroudi P, Cristea IM, Zakian VA, Capra JA, Sabouri N
(2016) PLoS Genet 12: e1006238
MeSH Terms: Binding Sites, DNA Helicases, DNA Replication, DNA-Directed DNA Polymerase, Genomic Instability, Multienzyme Complexes, Protein Binding, S Phase, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added April 18, 2017
Replicative DNA helicases expose the two strands of the double helix to the replication apparatus, but accessory helicases are often needed to help forks move past naturally occurring hard-to-replicate sites, such as tightly bound proteins, RNA/DNA hybrids, and DNA secondary structures. Although the Schizosaccharomyces pombe 5'-to-3' DNA helicase Pfh1 is known to promote fork progression, its genomic targets, dynamics, and mechanisms of action are largely unknown. Here we address these questions by integrating genome-wide identification of Pfh1 binding sites, comprehensive analysis of the effects of Pfh1 depletion on replication and DNA damage, and proteomic analysis of Pfh1 interaction partners by immunoaffinity purification mass spectrometry. Of the 621 high confidence Pfh1-binding sites in wild type cells, about 40% were sites of fork slowing (as marked by high DNA polymerase occupancy) and/or DNA damage (as marked by high levels of phosphorylated H2A). The replication and integrity of tRNA and 5S rRNA genes, highly transcribed RNA polymerase II genes, and nucleosome depleted regions were particularly Pfh1-dependent. The association of Pfh1 with genomic integrity at highly transcribed genes was S phase dependent, and thus unlikely to be an artifact of high transcription rates. Although Pfh1 affected replication and suppressed DNA damage at discrete sites throughout the genome, Pfh1 and the replicative DNA polymerase bound to similar extents to both Pfh1-dependent and independent sites, suggesting that Pfh1 is proximal to the replication machinery during S phase. Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner. Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate sites. These data provide insight into mechanisms by which this evolutionarily conserved helicase helps preserve genome integrity.
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10 MeSH Terms
The Tubulation Activity of a Fission Yeast F-BAR Protein Is Dispensable for Its Function in Cytokinesis.
McDonald NA, Takizawa Y, Feoktistova A, Xu P, Ohi MD, Vander Kooi CW, Gould KL
(2016) Cell Rep 14: 534-546
MeSH Terms: Animals, COS Cells, Cercopithecus aethiops, Crystallography, X-Ray, Cytokinesis, Cytoskeletal Proteins, Dimerization, Liposomes, Microscopy, Electron, Protein Structure, Tertiary, Recombinant Proteins, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added February 4, 2016
F-BAR proteins link cellular membranes to the actin cytoskeleton in many biological processes. Here we investigated the function of the Schizosaccharomyces pombe Imp2 F-BAR domain in cytokinesis and find that it is critical for Imp2's role in contractile ring constriction and disassembly. To understand mechanistically how the F-BAR domain functions, we determined its structure, elucidated how it interacts with membranes, and identified an interaction between dimers that allows helical oligomerization and membrane tubulation. Using mutations that block either membrane binding or tubulation, we find that membrane binding is required for Imp2's cytokinetic function but that oligomerization and tubulation, activities often deemed central to F-BAR protein function, are dispensable. Accordingly, F-BARs that do not have the capacity to tubulate membranes functionally substitute for the Imp2 F-BAR, establishing that its major role is as a cell-cycle-regulated bridge between the membrane and Imp2 protein partners, rather than as a driver of membrane curvature.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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13 MeSH Terms
Temporal Regulation of Lipin Activity Diverged to Account for Differences in Mitotic Programs.
Makarova M, Gu Y, Chen JS, Beckley JR, Gould KL, Oliferenko S
(2016) Curr Biol 26: 237-243
MeSH Terms: Cell Nucleus, Cell Nucleus Division, Chromosome Segregation, Mitosis, Organic Chemicals, Schizosaccharomyces
Show Abstract · Added February 4, 2016
Eukaryotes remodel the nucleus during mitosis using a variety of mechanisms that differ in the timing and the extent of nuclear envelope (NE) breakdown. Here, we probe the principles enabling this functional diversity by exploiting the natural divergence in NE management strategies between the related fission yeasts Schizosaccharomyces pombe and Schizosaccharomyces japonicus [1-3]. We show that inactivation of Ned1, the phosphatidic acid phosphatase of the lipin family, by CDK phosphorylation is both necessary and sufficient to promote NE expansion required for "closed" mitosis in S. pombe. In contrast, Ned1 is not regulated during division in S. japonicus, thus limiting membrane availability and necessitating NE breakage. Interspecies gene swaps result in phenotypically normal divisions with the S. japonicus lipin acquiring an S. pombe-like mitotic phosphorylation pattern. Our results provide experimental evidence for the mitotic regulation of phosphatidic acid flux and suggest that the regulatory networks governing lipin activity diverged in evolution to give rise to strikingly dissimilar mitotic programs.
Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.
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6 MeSH Terms
Oligomerization but Not Membrane Bending Underlies the Function of Certain F-BAR Proteins in Cell Motility and Cytokinesis.
McDonald NA, Vander Kooi CW, Ohi MD, Gould KL
(2015) Dev Cell 35: 725-36
MeSH Terms: Actin Cytoskeleton, Carrier Proteins, Cell Cycle Proteins, Cell Membrane, Cytokinesis, Cytoskeletal Proteins, Humans, Protein Multimerization, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added February 3, 2016
F-BAR proteins function in diverse cellular processes by linking membranes to the actin cytoskeleton. Through oligomerization, multiple F-BAR domains can bend membranes into tubules, though the physiological importance of F-BAR-to-F-BAR assemblies is not yet known. Here, we investigate the F-BAR domain of the essential cytokinetic scaffold, Schizosaccharomyces pombe Cdc15, during cytokinesis. Challenging a widely held view that membrane deformation is a fundamental property of F-BARs, we report that the Cdc15 F-BAR binds, but does not deform, membranes in vivo or in vitro, and six human F-BAR domains-including those from Fer and RhoGAP4-share this property. Nevertheless, tip-to-tip interactions between F-BAR dimers are critical for Cdc15 oligomerization and high-avidity membrane binding, stabilization of contractile ring components at the medial cortex, and the fidelity of cytokinesis. F-BAR oligomerization is also critical for Fer and RhoGAP4 physiological function, demonstrating its broad importance to F-BAR proteins that function without membrane bending.
Copyright © 2015 Elsevier Inc. All rights reserved.
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10 MeSH Terms
The DYRK-family kinase Pom1 phosphorylates the F-BAR protein Cdc15 to prevent division at cell poles.
Ullal P, McDonald NA, Chen JS, Lo Presti L, Roberts-Galbraith RH, Gould KL, Martin SG
(2015) J Cell Biol 211: 653-68
MeSH Terms: Actomyosin, Cell Cycle Proteins, Cell Division, Cytokinesis, Cytoskeletal Proteins, GTP-Binding Proteins, Phosphorylation, Protein Kinases, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Schizosaccharomyces, Schizosaccharomyces pombe Proteins
Show Abstract · Added February 4, 2016
Division site positioning is critical for both symmetric and asymmetric cell divisions. In many organisms, positive and negative signals cooperate to position the contractile actin ring for cytokinesis. In rod-shaped fission yeast Schizosaccharomyces pombe cells, division at midcell is achieved through positive Mid1/anillin-dependent signaling emanating from the central nucleus and negative signals from the dual-specificity tyrosine phosphorylation-regulated kinase family kinase Pom1 at the cell poles. In this study, we show that Pom1 directly phosphorylates the F-BAR protein Cdc15, a central component of the cytokinetic ring. Pom1-dependent phosphorylation blocks Cdc15 binding to paxillin Pxl1 and C2 domain protein Fic1 and enhances Cdc15 dynamics. This promotes ring sliding from cell poles, which prevents septum assembly at the ends of cells with a displaced nucleus or lacking Mid1. Pom1 also slows down ring constriction. These results indicate that a strong negative signal from the Pom1 kinase at cell poles converts Cdc15 to its closed state, destabilizes the actomyosin ring, and thus promotes medial septation.
© 2015 Ullal et al.
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12 MeSH Terms