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Fanconi anemia mitosis

Kurt Engeland
Activation of the p53 tumor suppressor can lead to cell cycle arrest. The key mechanism of p53-mediated arrest is transcriptional downregulation of many cell cycle genes. In recent years it has become evident that p53-dependent repression is controlled by the p53-p21-DREAM-E2F/CHR pathway (p53-DREAM pathway). DREAM is a transcriptional repressor that binds to E2F or CHR promoter sites. Gene regulation and deregulation by DREAM shares many mechanistic characteristics with the retinoblastoma pRB tumor suppressor that acts through E2F elements...
November 10, 2017: Cell Death and Differentiation
Daniela Kramer, Nadine Stark, Ramona Schulz-Heddergott, Norman Erytch, Shelley Edmunds, Laura Roßmann, Holger Bastians, Nicole Concin, Ute M Moll, Matthias Dobbelstein
All current regimens for treating ovarian cancer center around carboplatin as standard first line. The HSP90 inhibitor ganetespib is currently being assessed in advanced clinical oncology trials. Thus, we tested the combined effects of ganetespib and carboplatin on a panel of 15 human ovarian cancer lines. Strikingly, the two drugs strongly synergized in cytotoxicity in tumor cells lacking wild-type p53. Mechanistically, ganetespib and carboplatin in combination, but not individually, induced persistent DNA damage causing massive global chromosome fragmentation...
February 2017: Cell Death and Differentiation
Heidi S Bretscher, Donald T Fox
Conserved DNA-damage responses (DDRs) sense genome damage and prevent mitosis of broken chromosomes. How cells lacking DDRs cope with broken chromosomes during mitosis is poorly understood. DDRs are frequently inactivated in cells with extra genomes (polyploidy), suggesting that study of polyploidy can reveal how cells with impaired DDRs/genome damage continue dividing. Here, we show that continued division and normal organ development occurs in polyploid, DDR-impaired Drosophila papillar cells. As papillar cells become polyploid, they naturally accumulate broken acentric chromosomes but do not apoptose/arrest the cell cycle...
June 6, 2016: Developmental Cell
Reyna Lucía Barajas Torres, Martín Daniel Domínguez Cruz, César Borjas Gutiérrez, María de Lourdes Ramírez Dueñas, María Teresa Magaña Torres, Juan Ramón González García
1,3-Butadiene, a colorless gas regularly used in the production of plastics, thermoplastic resins, and styrene-butadiene rubber, poses an increased leukemia mortality risk to workers in this field. 1,3-Butadiene is also produced by incomplete combustion of motor fuels or by tobacco smoking. It is absorbed principally through the respiratory system and metabolized by several enzymes rendering 1,2:3,4-diepoxybutane (DEB), which has the highest genotoxic potency of all metabolites of 1,3-butadiene. DEB is considered a carcinogen mainly due to its high potential as clastogen, which induces structural chromosome aberrations such as sister chromatid exchanges, chromosomal breaks, and micronuclei...
2016: Cytogenetic and Genome Research
Audrey Magron, Sabine Elowe, Madeleine Carreau
The Fanconi anemia (FA) proteins are involved in a signaling network that assures the safeguard of chromosomes. To understand the function of FA proteins in cellular division events, we investigated the interaction between Stathmin-1 (STMN1) and the FA group C (FANCC) protein. STMN1 is a ubiquitous cytosolic protein that regulates microtubule dynamics. STMN1 activities are regulated through phosphorylation-dephosphorylation mechanisms that control assembly of the mitotic spindle, and dysregulation of STMN1 phosphorylation is associated with mitotic aberrancies leading to chromosome instability and cancer progression...
2015: PloS One
Alfredo Rodríguez, Leda Torres, Ulises Juárez, David Sosa, Eugenio Azpeitia, Benilde García-de Teresa, Edith Cortés, Rocío Ortíz, Ana M Salazar, Patricia Ostrosky-Wegman, Luis Mendoza, Sara Frías
BACKGROUND: The FA/BRCA pathway repairs DNA interstrand crosslinks. Mutations in this pathway cause Fanconi anemia (FA), a chromosome instability syndrome with bone marrow failure and cancer predisposition. Upon DNA damage, normal and FA cells inhibit the cell cycle progression, until the G2/M checkpoint is turned off by the checkpoint recovery, which becomes activated when the DNA damage has been repaired. Interestingly, highly damaged FA cells seem to override the G2/M checkpoint. In this study we explored with a Boolean network model and key experiments whether checkpoint recovery activation occurs in FA cells with extensive unrepaired DNA damage...
2015: Theoretical Biology & Medical Modelling
Zahi Abdul-Sater, Donna Cerabona, Elizabeth Sierra Potchanant, Zejin Sun, Rikki Enzor, Ying He, Kent Robertson, W Scott Goebel, Grzegorz Nalepa
The Fanconi anemia (FA/BRCA) signaling network controls multiple genome-housekeeping checkpoints, from interphase DNA repair to mitosis. The in vivo role of abnormal cell division in FA remains unknown. Here, we quantified the origins of genomic instability in FA patients and mice in vivo and ex vivo. We found that both mitotic errors and interphase DNA damage significantly contribute to genomic instability during FA-deficient hematopoiesis and in nonhematopoietic human and murine FA primary cells. Super-resolution microscopy coupled with functional assays revealed that FANCA shuttles to the pericentriolar material to regulate spindle assembly at mitotic entry...
December 2015: Experimental Hematology
Robin Mjelle, Siv Anita Hegre, Per Arne Aas, Geir Slupphaug, Finn Drabløs, Pål Saetrom, Hans E Krokan
Maintenance of a genome requires DNA repair integrated with chromatin remodeling. We have analyzed six transcriptome data sets and one data set on translational regulation of known DNA repair and remodeling genes in synchronized human cells. These data are available through our new database: Genes that have similar transcription profiles in at least two of our data sets generally agree well with known protein profiles. In brief, long patch base excision repair (BER) is enriched for S phase genes, whereas short patch BER uses genes essentially equally expressed in all cell cycle phases...
June 2015: DNA Repair
Marieke Aarts, Ilirjana Bajrami, Maria T Herrera-Abreu, Richard Elliott, Rachel Brough, Alan Ashworth, Christopher J Lord, Nicholas C Turner
WEE1 kinase regulates CDK1 and CDK2 activity to facilitate DNA replication during S-phase and to prevent unscheduled entry into mitosis. WEE1 inhibitors synergize with DNA-damaging agents that arrest cells in S-phase by triggering direct mitotic entry without completing DNA synthesis, resulting in catastrophic chromosome fragmentation and apoptosis. Here, we investigated how WEE1 inhibition could be best exploited for cancer therapy by performing a functional genetic screen to identify novel determinants of sensitivity to WEE1 inhibition...
April 2015: Molecular Cancer Therapeutics
Bertha Molina, Francesco Marchetti, Laura Gómez, Sandra Ramos, Leda Torres, Rocio Ortiz, Mario Altamirano-Lozano, Alessandra Carnevale, Sara Frias
Fanconi's anemia (FA) is a recessive disease; 16 genes are currently recognized in FA. FA proteins participate in the FA/BRCA pathway that plays a crucial role in the repair of DNA damage induced by crosslinking compounds. Hydroxyurea (HU) is an agent that induces replicative stress by inhibiting ribonucleotide reductase (RNR), which synthesizes deoxyribonucleotide triphosphates (dNTPs) necessary for DNA replication and repair. HU is known to activate the FA pathway; however, its clastogenic effects are not well characterized...
June 2015: Environmental and Molecular Mutagenesis
H Kenny Kuo, Susan McMahan, Christopher M Rota, Kathryn P Kohl, Jeff Sekelsky
Several helicases function during repair of double-strand breaks and handling of blocked or stalled replication forks to promote pathways that prevent formation of crossovers. Among these are the Bloom syndrome helicase BLM and the Fanconi anemia group M (FANCM) helicase. To better understand functions of these helicases, we compared phenotypes of Drosophila melanogaster Blm and Fancm mutants. As previously reported for BLM, FANCM has roles in responding to several types of DNA damage in preventing mitotic and meiotic crossovers and in promoting the synthesis-dependent strand annealing pathway for repair of a double-strand gap...
November 2014: Genetics
Bárbara Alcaraz Silva, Jessica R Stambaugh, Kyoko Yokomori, Jagesh V Shah, Michael W Berns
Chromosome ends contain nucleoprotein structures known as telomeres. Damage to chromosome ends during interphase elicits a DNA damage response (DDR) resulting in cell cycle arrest. However, little is known regarding the signaling from damaged chromosome ends (designated here as "TIPs") during mitosis. In the present study, we investigated the consequences of DNA damage induced at a single TIP in mitosis. We used laser microirradiation to damage mitotic TIPs or chromosome arms (non-TIPs) in PtK2 kidney epithelial cells...
August 15, 2014: Journal of Biological Chemistry
Aleksandra M Koczorowska, Aneta Białkowska, Katarzyna Kluzek, Małgorzata Z Zdzienicka
The Fanconi anemia (FA) pathway is one of the DNA repair systems involved in removal of DNA crosslinks. Proteins which belong to this pathway are crucial to the protection of genetic information, whereas disturbances in their function have serious implications for the whole organism. Biallelic mutations in FA genes are the cause of Fanconi anemia - a genetic disease which manifests itself through numerous congenital abnormalities, chromosomal instability and increased predisposition to cancer. The FA pathway is composed of fifteen proteins...
2014: Postȩpy Higieny i Medycyny Doświadczalnej
Grzegorz Nalepa, D Wade Clapp
Fanconi anemia (FA) is a complex heterogenic disorder of genomic instability, bone marrow failure, cancer predisposition, and congenital malformations. The FA signaling network orchestrates the DNA damage recognition and repair in interphase as well as proper execution of mitosis. Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis. Thus, the FA genes function as guardians of genome stability throughout the cell cycle...
2014: F1000Prime Reports
Andreja Leskovac, Sandra Petrovic, Marija Guc-Scekic, Dragana Vujic, Gordana Joksic
PURPOSE: As the Fanconi anemia (FA) pathway is required for appropriate cell cycle progression through mitosis and the completion of cell division, the aim of the present study was to determine the destiny of FA cells after irradiation in vitro and to elucidate any difference in radiosensitivity between FA and control cells. MATERIALS AND METHODS: Analyses of phosphorylated histone H2AX (γ-H2AX) foci, micronuclei formation and cell cycle analysis were performed in unirradiated (0 min) and irradiated primary FA fibroblasts and in a control group at different post-irradiation times (30 min, 2 h, 5 h and 24 h)...
May 2014: International Journal of Radiation Biology
Xiaoli Li, Liang Li, Jie Li, Jared Sipple, Jonathan Schick, Parinda A Mehta, Stella M Davies, Biplab Dasgupta, Ronald R Waclaw, Qishen Pang
AIMS: This study seeks at investigating the cause of hydrocephalus, and at identifying therapeutic targets for the prevention of hydrocephalus. RESULTS: In this study, we show that inactivation of the Foxo3a gene in two mouse models of Fanconi anemia (FA) leads to the development of hydrocephalus in late embryonic stage and after birth. More than 50% of Foxo3a(-/-) Fancc(-/-) or Foxo3a(-/-) Fancd2(-/-) mice die during embryonic development or within 6 months of life as a result of hydrocephalus characterized by cranial distortion, dilation of the ventricular system, reduced thickness of the cerebral cortex, and disorganization of the ependymal cilia and subcommissural organ...
October 20, 2014: Antioxidants & Redox Signaling
Luc Friboulet, Sophie Postel-Vinay, Tony Sourisseau, Julien Adam, Annabelle Stoclin, Florence Ponsonnailles, Nicolas Dorvault, Frédéric Commo, Patrick Saulnier, Sophie Salome-Desmoulez, Géraldine Pottier, Fabrice André, Guido Kroemer, Jean-Charles Soria, Ken André Olaussen
ERCC1 (excision repair cross-complementation group 1) plays essential roles in the removal of DNA intrastrand crosslinks by nucleotide excision repair, and that of DNA interstrand crosslinks by the Fanconi anemia (FA) pathway and homology-directed repair processes (HDR). The function of ERCC1 thus impacts on the DNA damage response (DDR), particularly in anticancer therapy when DNA damaging agents are employed. ERCC1 expression has been proposed as a predictive biomarker of the response to platinum-based therapy...
October 15, 2013: Cell Cycle
Grzegorz Nalepa, Rikki Enzor, Zejin Sun, Christophe Marchal, Su-Jung Park, Yanzhu Yang, Laura Tedeschi, Stephanie Kelich, Helmut Hanenberg, D Wade Clapp
Fanconi anemia (FA) is a heterogenous genetic disease with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair; however, it is incompletely understood why FA-deficient cells also develop gross aneuploidy, leading to cancer. Here, we systematically evaluated the role of the FA proteins in chromosome segregation through functional RNAi screens and analysis of primary cells from patients with FA. We found that FA signaling is essential for the spindle assembly checkpoint and is therefore required for high-fidelity chromosome segregation and prevention of aneuploidy...
September 2013: Journal of Clinical Investigation
Dorian R A Swarts, Leander Van Neste, Mieke E R Henfling, Ivo Eijkenboom, Paul P Eijk, Marie-Louise van Velthuysen, Aryan Vink, Marco Volante, Bauke Ylstra, Wim Van Criekinge, Manon van Engeland, Frans C S Ramaekers, Ernst-Jan M Speel
Pulmonary carcinoids comprise a well-differentiated subset of neuroendocrine tumors usually associated with a favorable prognosis, but mechanisms underlying disease progression are poorly understood. In an explorative approach to identify pathways associated with progression, we compared gene expression profiles of tumors from five patients with a favorable and five with a poor disease outcome. Differentially expressed genes were validated using quantitative real-time PCR on 65 carcinoid tumors, in combination with survival analysis...
December 2013: Carcinogenesis
Sunshin Kim, Soo Kyung Hwang, Mihee Lee, Heejin Kwak, Kook Son, Jiha Yang, Sung Hak Kim, Chang-Hun Lee
Fanconi anemia (FA) proteins are known to play roles in the cellular response to DNA interstrand cross-linking lesions; however, several reports have suggested that FA proteins play additional roles. To elucidate novel functions of FA proteins, we used yeast two-hybrid screening to identify binding partners of the Fanconi anemia complementation group A (FANCA) protein. The candidate proteins included never-in-mitosis-gene A (NIMA)-related kinase 2 (Nek2), which functions in the maintenance of centrosome integrity...
September 2013: International Journal of Biochemistry & Cell Biology
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