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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
Clinical and Genome-Wide Analysis of Cisplatin-Induced Peripheral Neuropathy in Survivors of Adult-Onset Cancer.
Dolan ME, El Charif O, Wheeler HE, Gamazon ER, Ardeshir-Rouhani-Fard S, Monahan P, Feldman DR, Hamilton RJ, Vaughn DJ, Beard CJ, Fung C, Kim J, Fossa SD, Hertz DL, Mushiroda T, Kubo M, Einhorn LH, Cox NJ, Travis LB, Platinum Study Group
(2017) Clin Cancer Res 23: 5757-5768
MeSH Terms: Adolescent, Adult, Age Factors, Age of Onset, Aged, Cancer Survivors, Cell Cycle Proteins, Cisplatin, Gene Expression Regulation, Neoplastic, Genome-Wide Association Study, Genotype, Humans, Hypertension, Male, Middle Aged, Neoplasm Proteins, Peripheral Nervous System Diseases, Polymorphism, Single Nucleotide, Risk Factors, Testicular Neoplasms
Show Abstract · Added October 27, 2017
Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs). TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial. Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; = 2 × 10), smoking (OR, 1.54; = 0.004), excess drinking (OR, 1.83; = 0.007), and hypertension (OR, 1.61; = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; = 2.6 × 10) and weight gain adjusted for years since treatment (OR per Δkg/m, 1.05; = 0.004). PrediXcan identified lower expressions of and and higher expression as associated with CisIPN ( value for each < 5 × 10) with replication of meeting significance criteria (Fisher combined = 0.0089). CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. .
©2017 American Association for Cancer Research.
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20 MeSH Terms
Chronic β-Cell Depolarization Impairs β-Cell Identity by Disrupting a Network of Ca-Regulated Genes.
Stancill JS, Cartailler JP, Clayton HW, O'Connor JT, Dickerson MT, Dadi PK, Osipovich AB, Jacobson DA, Magnuson MA
(2017) Diabetes 66: 2175-2187
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Calcium, Calcium Signaling, Cell Adhesion, Cell Cycle Proteins, Cell Lineage, Cell Polarity, Gene Expression, Gene Expression Regulation, Insulin-Secreting Cells, KATP Channels, Mice, Pancreatic Polypeptide-Secreting Cells, S100 Calcium Binding Protein A6, S100 Calcium-Binding Protein A4, S100 Proteins, Sulfonylurea Receptors
Show Abstract · Added June 2, 2017
We used mice lacking , a key component of the β-cell K-channel, to analyze the effects of a sustained elevation in the intracellular Ca concentration ([Ca]) on β-cell identity and gene expression. Lineage tracing analysis revealed the conversion of β-cells lacking into pancreatic polypeptide cells but not to α- or δ-cells. RNA-sequencing analysis of FACS-purified β-cells confirmed an increase in gene expression and revealed altered expression of more than 4,200 genes, many of which are involved in Ca signaling, the maintenance of β-cell identity, and cell adhesion. The expression of and , two highly upregulated genes, is closely correlated with membrane depolarization, suggesting their use as markers for an increase in [Ca] Moreover, a bioinformatics analysis predicts that many of the dysregulated genes are regulated by common transcription factors, one of which, , was confirmed to be directly controlled by Ca influx in β-cells. Interestingly, among the upregulated genes is , a putative marker of β-cell dedifferentiation, and other genes associated with β-cell failure. Taken together, our results suggest that chronically elevated β-cell [Ca] in islets contributes to the alteration of β-cell identity, islet cell numbers and morphology, and gene expression by disrupting a network of Ca-regulated genes.
© 2017 by the American Diabetes Association.
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18 MeSH Terms
ETAA1 acts at stalled replication forks to maintain genome integrity.
Bass TE, Luzwick JW, Kavanaugh G, Carroll C, Dungrawala H, Glick GG, Feldkamp MD, Putney R, Chazin WJ, Cortez D
(2016) Nat Cell Biol 18: 1185-1195
MeSH Terms: Adaptor Proteins, Signal Transducing, Antigens, Surface, Ataxia Telangiectasia Mutated Proteins, Carrier Proteins, Cell Cycle Proteins, Cell Line, DNA Damage, DNA Replication, DNA-Binding Proteins, Genome, Human, Genomic Instability, Humans, Protein-Serine-Threonine Kinases, Proteomics, Signal Transduction
Show Abstract · Added April 18, 2017
The ATR checkpoint kinase coordinates cellular responses to DNA replication stress. Budding yeast contain three activators of Mec1 (the ATR orthologue); however, only TOPBP1 is known to activate ATR in vertebrates. We identified ETAA1 as a replication stress response protein in two proteomic screens. ETAA1-deficient cells accumulate double-strand breaks, sister chromatid exchanges, and other hallmarks of genome instability. They are also hypersensitive to replication stress and have increased frequencies of replication fork collapse. ETAA1 contains two RPA-interaction motifs that localize ETAA1 to stalled replication forks. It also interacts with several DNA damage response proteins including the BLM/TOP3α/RMI1/RMI2 and ATR/ATRIP complexes. It binds ATR/ATRIP directly using a motif with sequence similarity to the TOPBP1 ATR-activation domain; and like TOPBP1, ETAA1 acts as a direct ATR activator. ETAA1 functions in parallel to the TOPBP1/RAD9/HUS1/RAD1 pathway to regulate ATR and maintain genome stability. Thus, vertebrate cells contain at least two ATR-activating proteins.
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15 MeSH Terms
Interaction of Gcn4 with target gene chromatin is modulated by proteasome function.
Howard GC, Tansey WP
(2016) Mol Biol Cell 27: 2735-41
MeSH Terms: Adenosine Triphosphatases, Basic-Leucine Zipper Transcription Factors, Cell Cycle Proteins, Chromatin, DNA-Binding Proteins, Molecular Chaperones, Proteasome Endopeptidase Complex, Proteolysis, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Transcription Factors, Transcriptional Activation, Ubiquitin, Ubiquitination, Valosin Containing Protein
Show Abstract · Added March 26, 2019
The ubiquitin-proteasome system (UPS) influences gene transcription in multiple ways. One way in which the UPS affects transcription centers on transcriptional activators, the function of which can be stimulated by components of the UPS that also trigger their destruction. Activation of transcription by the yeast activator Gcn4, for example, is attenuated by mutations in the ubiquitin ligase that mediates Gcn4 ubiquitylation or by inhibition of the proteasome, leading to the idea that ubiquitin-mediated proteolysis of Gcn4 is required for its activity. Here we probe the steps in Gcn4 activity that are perturbed by disruption of the UPS. We show that the ubiquitylation machinery and the proteasome control different steps in Gcn4 function and that proteasome activity is required for the ability of Gcn4 to bind to its target genes in the context of chromatin. Curiously, the effect of proteasome inhibition on Gcn4 activity is suppressed by mutations in the ubiquitin-selective chaperone Cdc48, revealing that proteolysis per se is not required for Gcn4 activity. Our data highlight the role of Cdc48 in controlling promoter occupancy by Gcn4 and support a model in which ubiquitylation of activators-not their destruction-is important for function.
© 2016 Howard and Tansey. 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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MeSH Terms
Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis.
Qin HD, Liao XY, Chen YB, Huang SY, Xue WQ, Li FF, Ge XS, Liu DQ, Cai Q, Long J, Li XZ, Hu YZ, Zhang SD, Zhang LJ, Lehrman B, Scott AF, Lin D, Zeng YX, Shugart YY, Jia WH
(2016) Am J Hum Genet 98: 709-27
MeSH Terms: Adult, Aged, Aged, 80 and over, Animals, Carcinogenesis, Carcinoma, Squamous Cell, Carrier Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, DNA Copy Number Variations, Esophageal Neoplasms, Esophageal Squamous Cell Carcinoma, Exome, Fas-Associated Death Domain Protein, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Humans, Male, Membrane Proteins, Mice, Mice, Inbred BALB C, MicroRNAs, Middle Aged, Mutation, Nerve Tissue Proteins, Prognosis, Selection, Genetic, Trans-Activators, Xenograft Model Antitumor Assays
Show Abstract · Added April 3, 2018
The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.
Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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32 MeSH Terms
Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170.
Dunning AM, Michailidou K, Kuchenbaecker KB, Thompson D, French JD, Beesley J, Healey CS, Kar S, Pooley KA, Lopez-Knowles E, Dicks E, Barrowdale D, Sinnott-Armstrong NA, Sallari RC, Hillman KM, Kaufmann S, Sivakumaran H, Moradi Marjaneh M, Lee JS, Hills M, Jarosz M, Drury S, Canisius S, Bolla MK, Dennis J, Wang Q, Hopper JL, Southey MC, Broeks A, Schmidt MK, Lophatananon A, Muir K, Beckmann MW, Fasching PA, Dos-Santos-Silva I, Peto J, Sawyer EJ, Tomlinson I, Burwinkel B, Marme F, Guénel P, Truong T, Bojesen SE, Flyger H, González-Neira A, Perez JI, Anton-Culver H, Eunjung L, Arndt V, Brenner H, Meindl A, Schmutzler RK, Brauch H, Hamann U, Aittomäki K, Blomqvist C, Ito H, Matsuo K, Bogdanova N, Dörk T, Lindblom A, Margolin S, Kosma VM, Mannermaa A, Tseng CC, Wu AH, Lambrechts D, Wildiers H, Chang-Claude J, Rudolph A, Peterlongo P, Radice P, Olson JE, Giles GG, Milne RL, Haiman CA, Henderson BE, Goldberg MS, Teo SH, Yip CH, Nord S, Borresen-Dale AL, Kristensen V, Long J, Zheng W, Pylkäs K, Winqvist R, Andrulis IL, Knight JA, Devilee P, Seynaeve C, Figueroa J, Sherman ME, Czene K, Darabi H, Hollestelle A, van den Ouweland AM, Humphreys K, Gao YT, Shu XO, Cox A, Cross SS, Blot W, Cai Q, Ghoussaini M, Perkins BJ, Shah M, Choi JY, Kang D, Lee SC, Hartman M, Kabisch M, Torres D, Jakubowska A, Lubinski J, Brennan P, Sangrajrang S, Ambrosone CB, Toland AE, Shen CY, Wu PE, Orr N, Swerdlow A, McGuffog L, Healey S, Lee A, Kapuscinski M, John EM, Terry MB, Daly MB, Goldgar DE, Buys SS, Janavicius R, Tihomirova L, Tung N, Dorfling CM, van Rensburg EJ, Neuhausen SL, Ejlertsen B, Hansen TV, Osorio A, Benitez J, Rando R, Weitzel JN, Bonanni B, Peissel B, Manoukian S, Papi L, Ottini L, Konstantopoulou I, Apostolou P, Garber J, Rashid MU, Frost D, EMBRACE, Izatt L, Ellis S, Godwin AK, Arnold N, Niederacher D, Rhiem K, Bogdanova-Markov N, Sagne C, Stoppa-Lyonnet D, Damiola F, GEMO Study Collaborators, Sinilnikova OM, Mazoyer S, Isaacs C, Claes KB, De Leeneer K, de la Hoya M, Caldes T, Nevanlinna H, Khan S, Mensenkamp AR, HEBON, Hooning MJ, Rookus MA, Kwong A, Olah E, Diez O, Brunet J, Pujana MA, Gronwald J, Huzarski T, Barkardottir RB, Laframboise R, Soucy P, Montagna M, Agata S, Teixeira MR, kConFab Investigators, Park SK, Lindor N, Couch FJ, Tischkowitz M, Foretova L, Vijai J, Offit K, Singer CF, Rappaport C, Phelan CM, Greene MH, Mai PL, Rennert G, Imyanitov EN, Hulick PJ, Phillips KA, Piedmonte M, Mulligan AM, Glendon G, Bojesen A, Thomassen M, Caligo MA, Yoon SY, Friedman E, Laitman Y, Borg A, von Wachenfeldt A, Ehrencrona H, Rantala J, Olopade OI, Ganz PA, Nussbaum RL, Gayther SA, Nathanson KL, Domchek SM, Arun BK, Mitchell G, Karlan BY, Lester J, Maskarinec G, Woolcott C, Scott C, Stone J, Apicella C, Tamimi R, Luben R, Khaw KT, Helland Å, Haakensen V, Dowsett M, Pharoah PD, Simard J, Hall P, García-Closas M, Vachon C, Chenevix-Trench G, Antoniou AC, Easton DF, Edwards SL
(2016) Nat Genet 48: 374-86
MeSH Terms: Base Sequence, Breast Neoplasms, Carrier Proteins, Cell Cycle Proteins, Chromosomes, Human, Pair 6, Estrogen Receptor alpha, Female, Gene Expression, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Phenotype, Polymorphism, Single Nucleotide, Protein Binding, Risk Factors
Show Abstract · Added April 3, 2018
We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
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