163 research outputs found
Pellman, Raymond J. (Birth, 1908-04-22)
No full textAddress: 1860 DenhamPg 42/1908/M W/Cinti/Ky/Dr. A. D. StaplefordOriginal record filed in drawer labeled 'PECK-PERKING'
A natural histone H2A variant lacking the Bub1 phosphorylation site and regulated depletion of centromeric histone CENP-A foster evolvability in <i>Candida albicans</i>
No full textEukaryotes have evolved elaborate mechanisms to ensure that chromosomes segregate with high fidelity during mitosis and meiosis, and yet specific aneuploidies can be adaptive during environmental stress. Here, we identify a chromatin-based system required for inducible aneuploidy in a human pathogen. Candida albicans utilizes chromosome missegregation to acquire tolerance to antifungal drugs and for nonmeiotic ploidy reduction after mating. We discovered that the ancestor of C. albicans and 2 related pathogens evolved a variant of histone 2A (H2A) that lacks the conserved phosphorylation site for kinetochore-associated Bub1 kinase, a key regulator of chromosome segregation. Using engineered strains, we show that the relative gene dosage of this variant versus canonical H2A controls the fidelity of chromosome segregation and the rate of acquisition of tolerance to antifungal drugs via aneuploidy. Furthermore, whole-genome chromatin precipitation analysis reveals that Centromere Protein A/ Centromeric Histone H3-like Protein (CENP-A/Cse4), a centromeric histone H3 variant that forms the platform of the eukaryotic kinetochore, is depleted from tetraploid-mating products relative to diploid parents and is virtually eliminated from cells exposed to aneuploidy-promoting cues. We conclude that genetically programmed and environmentally induced changes in chromatin can confer the capacity for enhanced evolvability via chromosome missegregation.</div
Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance
No full textWe report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.Max A. Tischfield, Hagit N. Baris, Chen Wu, Guenther Rudolph, Lionel Van Maldergem, Wei He, Wai-Man Chan, Caroline Andrews, Joseph L. Demer, Richard L. Robertson, David A. Mackey, Jonathan B. Ruddle, Thomas D. Bird, Irene Gottlob, Christina Pieh, Elias I. Traboulsi, Scott L. Pomeroy, David G. Hunter, Janet S. Soul, Anna Newlin, Louise J. Sabol, Edward J. Doherty, Clara E. de Uzca´ tegui, Nicolas de Uzca´ tegui, Mary Louise Z. Collins, Emin C. Sener, Bettina Wabbels, Heide Hellebrand, Thomas Meitinger, Teresa de Berardinis, Adriano Magli, Costantino Schiavi, Marco Pastore-Trossello, Feray Koc, Agnes M. Wong, Alex V. Levin, Michael T. Geraghty, Maria Descartes, Maree Flaherty, Robyn V. Jamieson, H.U. Møller, Ingo Meuthen, David F. Callen, Janet Kerwin, Susan Lindsay, Alfons Meindl, Mohan L. Gupta, Jr., David Pellman, and Elizabeth C. Engl
Dividing the spoils of growth and the cell cycle: The fission yeast as a model for the study of cytokinesis
No full textCytokinesis is the final stage of the cell cycle, and ensures completion of both genome segregation and organelle distribution to the daughter cells. Cytokinesis requires the cell to solve a spatial problem (to divide in the correct place, orthogonally to the plane of chromosome segregation) and a temporal problem (to coordinate cytokinesis with mitosis). Defects in the spatiotemporal control of cytokinesis may cause cell death, or increase the risk of tumor formation [Fujiwara et al., 2005 (Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D. 2005. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437:1043–1047); reviewed by Ganem et al., 2007 (Ganem NJ, Storchova Z, Pellman D. 2007. Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev 17:157–162.)]. Asymmetric cytokinesis, which permits the generation of two daughter cells that differ in their shape, size and properties, is important both during development, and for cellular homeostasis in multicellular organisms [reviewed by Li, 2007 (Li R. 2007. Cytokinesis in development and disease: variations on a common theme. Cell Mol Life Sci 64:3044–3058)]. The principal focus of this review will be the mechanisms of cytokinesis in the mitotic cycle of the yeast Schizosaccharomyces pombe. This simple model has contributed significantly to our understanding of how the cell cycle is regulated, and serves as an excellent model for studying aspects of cytokinesis. Here we will discuss the state of our knowledge of how the contractile ring is assembled and disassembled, how it contracts, and what we know of the regulatory mechanisms that control these events and assure their coordination with chromosome segregation.UPSI
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The Function and Regulation of REV7 in DNA Repair Pathway Choice
No full textDNA damage is a major threat facing our cells on a daily basis. Failure to properly repair
damaged DNA can lead to the development of cancer. REV7 is a small protein that is essential
for two highly distinct DNA repair pathways: double strand break (DSB) repair and translesion
DNA synthesis (TLS). While the TLS function of REV7 has been known for many years, its
involvement in DSB repair and potentially other pathways in just beginning to be unraveled. In
this work I investigate the function and regulation or REV7 in two new contexts, the Fanconi
Anemia (FA) pathway and in DSB repair. I demonstrate the existence of the novel REV7 binding
partner FAM35A/SHLD2 and show that it is an essential player specifically in the DSB repair
branch of REV7 function. I further reveal a unique mechanism of regulation of REV7 dictated by
stable conformational changes, which are controlled in part by the ATPase TRIP13 and its
adaptor subunit p31. By actively remodeling REV7, TRIP13-p31 promote the inactivation of
REV7-dependent complexes, promoting the usage of higher-fidelity alternatives to REV7-
dependent pathways. Overall, this work reveals a new degree of complexity and importance of
the REV7 protein in controlling DNA repair pathway choice in multiple contexts.Medical SciencesMedical Science
Symmetry Breaking: Scaffold Plays Matchmaker for Polarity Signaling Proteins
No full textSummaryMany cell types can spontaneously polarize even in the absence of specific positional cues. In budding yeast, this symmetry-breaking polarization depends on a scaffold protein called Bem1p. A recent study defines Bem1p's molecular function during symmetry breaking
Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 Lys27 trimethylation.
No full textAuthor Correction: Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing
No full textauthor correctio
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