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https://www.readbyqxmd.com/read/28396698/internal-modifications-in-the-cenp-a-nucleosome-modulate-centromeric-dynamics
#1
Minh Bui, Mary Pitman, Arthur Nuccio, Serene Roque, Paul Gregory Donlin-Asp, Aleksandra Nita-Lazar, Garegin A Papoian, Yamini Dalal
BACKGROUND: Posttranslational modifications of core histones are correlated with changes in transcriptional status, chromatin fiber folding, and nucleosome dynamics. However, within the centromere-specific histone H3 variant CENP-A, few modifications have been reported, and their functions remain largely unexplored. In this multidisciplinary report, we utilize in silico computational and in vivo approaches to dissect lysine 124 of human CENP-A, which was previously reported to be acetylated in advance of replication...
2017: Epigenetics & Chromatin
https://www.readbyqxmd.com/read/28377371/molecular-basis-for-cdk1-regulated-timing-of-mis18-complex-assembly-and-cenp-a-deposition
#2
Frances Spiller, Bethan Medina-Pritchard, Maria Alba Abad, Martin A Wear, Oscar Molina, William C Earnshaw, A Arockia Jeyaprakash
The centromere, a chromosomal locus that acts as a microtubule attachment site, is epigenetically specified by the enrichment of CENP-A nucleosomes. Centromere maintenance during the cell cycle requires HJURP-mediated CENP-A deposition, a process regulated by the Mis18 complex (Mis18α/Mis18β/Mis18BP1). Spatial and temporal regulation of Mis18 complex assembly is crucial for its centromere association and function. Here, we provide the molecular basis for the assembly and regulation of the Mis18 complex. We show that the N-terminal region of Mis18BP1 spanning amino acid residues 20-130 directly interacts with Mis18α/β to form the Mis18 complex...
April 4, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28356341/essential-role-for-centromeric-factors-following-p53-loss-and-oncogenic-transformation
#3
Dan Filipescu, Monica Naughtin, Katrina Podsypanina, Vincent Lejour, Laurence Wilson, Zachary A Gurard-Levin, Guillermo A Orsi, Iva Simeonova, Eleonore Toufektchan, Laura D Attardi, Franck Toledo, Geneviève Almouzni
In mammals, centromere definition involves the histone variant CENP-A (centromere protein A), deposited by its chaperone, HJURP (Holliday junction recognition protein). Alterations in this process impair chromosome segregation and genome stability, which are also compromised by p53 inactivation in cancer. Here we found that CENP-A and HJURP are transcriptionally up-regulated in p53-null human tumors. Using an established mouse embryonic fibroblast (MEF) model combining p53 inactivation with E1A or HRas-V12 oncogene expression, we reproduced a similar up-regulation of HJURP and CENP-A...
March 29, 2017: Genes & Development
https://www.readbyqxmd.com/read/28321116/chromosome-biology-trimethylation-of-cenp-a-supports-mitotic-fidelity
#4
Paulina Strzyz
No abstract text is available yet for this article.
March 21, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28286049/insulin-signaling-regulates-the-foxm1-plk1-cenp-a-pathway-to-promote-adaptive-pancreatic-%C3%AE-%C3%A2-cell-proliferation
#5
Jun Shirakawa, Megan Fernandez, Tomozumi Takatani, Abdelfattah El Ouaamari, Prapaporn Jungtrakoon, Erin R Okawa, Wei Zhang, Peng Yi, Alessandro Doria, Rohit N Kulkarni
Investigation of cell-cycle kinetics in mammalian pancreatic β cells has mostly focused on transition from the quiescent (G0) to G1 phase. Here, we report that centromere protein A (CENP-A), which is required for chromosome segregation during the M-phase, is necessary for adaptive β cell proliferation. Receptor-mediated insulin signaling promotes DNA-binding activity of FoxM1 to regulate expression of CENP-A and polo-like kinase-1 (PLK1) by modulating cyclin-dependent kinase-1/2. CENP-A deposition at the centromere is augmented by PLK1 to promote mitosis, while knocking down CENP-A limits β cell proliferation and survival...
April 4, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28266506/%C3%AE-amino-trimethylation-of-cenp-a-by-nrmt-is-required-for-full-recruitment-of-the-centromere
#6
Kizhakke M Sathyan, Daniele Fachinetti, Daniel R Foltz
Centromeres are unique chromosomal domains that control chromosome segregation, and are epigenetically specified by the presence of the CENP-A containing nucleosomes. CENP-A governs centromere function by recruiting the constitutive centromere associated network (CCAN) complex. The features of the CENP-A nucleosome necessary to distinguish centromeric chromatin from general chromatin are not completely understood. Here we show that CENP-A undergoes α-amino trimethylation by the enzyme NRMT in vivo. We show that α-amino trimethylation of the CENP-A tail contributes to cell survival...
March 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28265097/stepwise-unfolding-supports-a-subunit-model-for-vertebrate-kinetochores
#7
Giulia Vargiu, Alexandr A Makarov, James Allan, Tatsuo Fukagawa, Daniel G Booth, William C Earnshaw
During cell division, interactions between microtubules and chromosomes are mediated by the kinetochore, a proteinaceous structure located at the primary constriction of chromosomes. In addition to the centromere histone centromere protein A (CENP-A), 15 other members of the constitutive centromere associated network (CCAN) participate in the formation of a chromatin-associated scaffold that supports kinetochore structure. We performed a targeted screen analyzing unfolded centrochromatin from CENP-depleted chromosomes...
March 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28235947/human-centromeric-cenp-a-chromatin-is-a-homotypic-octameric-nucleosome-at-all-cell-cycle-points
#8
Yael Nechemia-Arbely, Daniele Fachinetti, Karen H Miga, Nikolina Sekulic, Gautam V Soni, Dong Hyun Kim, Adeline K Wong, Ah Young Lee, Kristen Nguyen, Cees Dekker, Bing Ren, Ben E Black, Don W Cleveland
Chromatin assembled with centromere protein A (CENP-A) is the epigenetic mark of centromere identity. Using new reference models, we now identify sites of CENP-A and histone H3.1 binding within the megabase, α-satellite repeat-containing centromeres of 23 human chromosomes. The overwhelming majority (97%) of α-satellite DNA is found to be assembled with histone H3.1-containing nucleosomes with wrapped DNA termini. In both G1 and G2 cell cycle phases, the 2-4% of α-satellite assembled with CENP-A protects DNA lengths centered on 133 bp, consistent with octameric nucleosomes with DNA unwrapping at entry and exit...
March 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28220502/variations-on-a-nucleosome-theme-the-structural-basis-of-centromere-function
#9
Olga Moreno-Moreno, Mònica Torras-Llort, Fernando Azorín
The centromere is a specialized chromosomal structure that dictates kinetochore assembly and, thus, is essential for accurate chromosome segregation. Centromere identity is determined epigenetically by the presence of a centromere-specific histone H3 variant, CENP-A, that replaces canonical H3 in centromeric chromatin. Here, we discuss recent work by Roulland et al. that identifies structural elements of the nucleosome as essential determinants of centromere function. In particular, CENP-A nucleosomes have flexible DNA ends due to the short αN helix of CENP-A...
February 21, 2017: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
https://www.readbyqxmd.com/read/28186195/cenp-a-chromatin-disassembly-in-stressed-and-senescent-murine-cells
#10
Sabrine Hédouin, Giacomo Grillo, Ivana Ivkovic, Guillaume Velasco, Claire Francastel
Centromeres are chromosomal domains essential for genomic stability. We report here the remarkable transcriptional and epigenetic perturbations at murine centromeres in genotoxic stress conditions. A strong and selective transcriptional activation of centromeric repeats is detected within hours. This is followed by disorganization of centromeres with striking delocalization of nucleosomal CENP-A, the key determinant of centromere identity and function, in a mechanism requiring active transcription of centromeric repeats, the DNA Damage Response (DDR) effector ATM and chromatin remodelers/histone chaperones...
February 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28167779/integrity-of-the-human-centromere-dna-repeats-is-protected-by-cenp-a-cenp-c-and-cenp-t
#11
Simona Giunta, Hironori Funabiki
Centromeres are highly specialized chromatin domains that enable chromosome segregation and orchestrate faithful cell division. Human centromeres are composed of tandem arrays of α-satellite DNA, which spans up to several megabases. Little is known about the mechanisms that maintain integrity of the long arrays of α-satellite DNA repeats. Here, we monitored centromeric repeat stability in human cells using chromosome-orientation fluorescent in situ hybridization (CO-FISH). This assay detected aberrant centromeric CO-FISH patterns consistent with sister chromatid exchange at the frequency of 5% in primary tissue culture cells, whereas higher levels were seen in several cancer cell lines and during replicative senescence...
February 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28158539/defects-in-methylation-of-arginine-37-on-cenp-a-cse4-are-compensated-by-the-ubiquitin-ligase-complex-ubr2-mub1
#12
Anke Samel, Thi Kim Loan Nguyen, Ann E Ehrenhofer-Murray
No abstract text is available yet for this article.
February 2, 2017: FEMS Yeast Research
https://www.readbyqxmd.com/read/28137567/mass-spectrometry-based-methodology-for-identification-of-native-histone-variant-modifications-from-mammalian-tissues-and-solid-tumors
#13
A G Nuccio, M Bui, Y Dalal, A Nita-Lazar
Histone posttranslational modifications (PTMs) are key epigenetic marks involved in gene silencing or activation. Histone modifications impact chromatin organization and transcriptional processes through the changes in charge density between histones and DNA. They also serve as recognition and binding sites for specific binding proteins. Histone tails and globular cores contain many basic amino acid residues, which are subject to various dynamic modifications, making the modification repertoire extremely diverse...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28094382/the-supercoiling-state-of-dna-determines-the-handedness-of-both-h3-and-cenp-a-nucleosomes
#14
R Vlijm, S H Kim, P L De Zwart, Y Dalal, C Dekker
Nucleosomes form the unit structure of the genome in eukaryotes, thereby constituting a fundamental tenet of chromatin biology. In canonical nucleosomes, DNA wraps around the histone octamer in a left-handed toroidal ramp. Here, in single-molecule magnetic tweezers studies of chaperone-assisted nucleosome assembly, we show that the handedness of the DNA wrapping around the nucleosome core is intrinsically ambidextrous, and depends on the pre-assembly supercoiling state of the DNA, i.e., it is not uniquely determined by the octameric histone core...
January 17, 2017: Nanoscale
https://www.readbyqxmd.com/read/28073008/cenp-a-modifications-on-ser68-and-lys124-are-dispensable-for-establishment-maintenance-and-long-term-function-of-human-centromeres
#15
Daniele Fachinetti, Glennis A Logsdon, Amira Abdullah, Evan B Selzer, Don W Cleveland, Ben E Black
CENP-A is a histone H3 variant key to epigenetic specification of mammalian centromeres. Using transient overexpression of CENP-A mutants, two recent reports in Developmental Cell proposed essential centromere functions for post-translational modifications of human CENP-A. Phosphorylation at Ser68 was proposed to have an essential role in CENP-A deposition at centromeres. Blockage of ubiquitination at Lys124 was proposed to abrogate localization of CENP-A to the centromere. Following gene inactivation and replacement in human cells, we demonstrate that CENP-A mutants that cannot be phosphorylated at Ser68 or ubiquitinated at Lys124 assemble efficiently at centromeres during G1, mediate early events in centromere establishment at an ectopic chromosomal locus, and maintain centromere function indefinitely...
January 9, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28069312/centromeres-drive-a-hard-bargain
#16
REVIEW
Leah F Rosin, Barbara G Mellone
Centromeres are essential chromosomal structures that mediate the accurate distribution of genetic material during meiotic and mitotic cell divisions. In most organisms, centromeres are epigenetically specified and propagated by nucleosomes containing the centromere-specific H3 variant, centromere protein A (CENP-A). Although centromeres perform a critical and conserved function, CENP-A and the underlying centromeric DNA are rapidly evolving. This paradox has been explained by the centromere drive hypothesis, which proposes that CENP-A is undergoing an evolutionary tug-of-war with selfish centromeric DNA...
January 7, 2017: Trends in Genetics: TIG
https://www.readbyqxmd.com/read/28059702/cdk-regulated-dimerization-of-m18bp1-on-a-mis18-hexamer-is-necessary-for-cenp-a-loading
#17
Dongqing Pan, Kerstin Klare, Arsen Petrovic, Annika Take, Kai Walstein, Priyanka Singh, Arnaud Rondelet, Alexander W Bird, Andrea Musacchio
Centromeres are unique chromosomal loci that promote the assembly of kinetochores, macromolecular complexes that bind spindle microtubules during mitosis. In most organisms, centromeres lack defined genetic features. Rather, they are specified epigenetically by a centromere-specific histone H3 variant, CENP-A. The Mis18 complex, comprising the Mis18α:Mis18β subcomplex and M18BP1, is crucial for CENP-A homeostasis. It recruits the CENP-A-specific chaperone HJURP to centromeres and primes it for CENP-A loading...
January 6, 2017: ELife
https://www.readbyqxmd.com/read/28017591/a-dual-inhibitory-mechanism-sufficient-to-maintain-cell-cycle-restricted-cenp-a-assembly
#18
Ana Stankovic, Lucie Y Guo, João F Mata, Dani L Bodor, Xing-Jun Cao, Aaron O Bailey, Jeffrey Shabanowitz, Donald F Hunt, Benjamin A Garcia, Ben E Black, Lars E T Jansen
Chromatin featuring the H3 variant CENP-A at the centromere is critical for its mitotic function and epigenetic maintenance. Assembly of centromeric chromatin is restricted to G1 phase through inhibitory action of Cdk1/2 kinases in other phases of the cell cycle. Here, we identify the two key targets sufficient to maintain cell-cycle control of CENP-A assembly. We uncovered a single phosphorylation site in the licensing factor M18BP1 and a cyclin A binding site in the CENP-A chaperone, HJURP, that mediated specific inhibitory phosphorylation...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/27940888/constitutive-centromere-associated-network-controls-centromere-drift-in-vertebrate-cells
#19
Tetsuya Hori, Naoko Kagawa, Atsushi Toyoda, Asao Fujiyama, Sadahiko Misu, Norikazu Monma, Fumiaki Makino, Kazuho Ikeo, Tatsuo Fukagawa
Centromeres are specified by sequence-independent epigenetic mechanisms, and the centromere position may drift at each cell cycle, but once this position is specified, it may not be frequently moved. Currently, it is unclear whether the centromere position is stable. To address this question, we systematically analyzed the position of nonrepetitive centromeres in 21 independent clones isolated from a laboratory stock of chicken DT40 cells using chromatin immunoprecipitation combined with massive parallel sequencing analysis with anti-CENP-A antibody...
January 2, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/27918550/selective-y-centromere-inactivation-triggers-chromosome-shattering-in-micronuclei-and-repair-by-non-homologous-end-joining
#20
Peter Ly, Levi S Teitz, Dong H Kim, Ofer Shoshani, Helen Skaletsky, Daniele Fachinetti, David C Page, Don W Cleveland
Chromosome missegregation into a micronucleus can cause complex and localized genomic rearrangements known as chromothripsis, but the underlying mechanisms remain unresolved. Here we developed an inducible Y centromere-selective inactivation strategy by exploiting a CENP-A/histone H3 chimaera to directly examine the fate of missegregated chromosomes in otherwise diploid human cells. Using this approach, we identified a temporal cascade of events that are initiated following centromere inactivation involving chromosome missegregation, fragmentation, and re-ligation that span three consecutive cell cycles...
January 2017: Nature Cell Biology
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