Xavier Renaudin, Filippo Rosselli
DNA interstrand cross-links (ICLs) represent a major barrier blocking DNA replication fork progression. ICL accumulation results in growth arrest and cell death-particularly in cell populations undergoing high replicative activity, such as cancer and leukemic cells. For this reason, agents able to induce DNA ICLs are widely used as chemotherapeutic drugs. However, ICLs are also generated in cells as byproducts of normal metabolic activities. Therefore, every cell must be capable of rescuing lCL-stalled replication forks while maintaining the genetic stability of the daughter cells in order to survive, replicate DNA and segregate chromosomes at mitosis...
May 25, 2020: Genes
Narasimha Kumar Karanam, Liang Hao-Ding, Asaithamby Aroumougame, Michael D Story
Tumor treating fields (TTFields) is a noninvasive physical modality of cancer therapy that applies low-intensity, intermediate frequency, and alternating electric fields to a tumor. Interference with mitosis was the first mechanism describing the effects of TTFields on cancer cells; however, TTFields was shown to not only reduce the rejoining of radiation-induced DNA double-strand breaks (DSBs), but to also induce DNA DSBs. The mechanism(s) by which TTFields generates DNA DSBs is related to the generation of replication stress including reduced expression of the DNA replication complex genes MCM6 and MCM10 and the Fanconi's Anemia pathway genes...
October 21, 2019: Translational Research: the Journal of Laboratory and Clinical Medicine
Michalis Fragkos, Viviana Barra, Tom Egger, Benoit Bordignon, Delphine Lemacon, Valeria Naim, Arnaud Coquelle
Dicer, an endoribonuclease best-known for its role in microRNA biogenesis and RNA interference pathway, has been shown to play a role in the DNA damage response and repair of double-stranded DNA breaks (DSBs) in mammalian cells. However, it remains unknown whether Dicer is also important to preserve genome integrity upon replication stress. To address this question, we focused our study on common fragile sites (CFSs), which are susceptible to breakage after replication stress. We show that inhibition of the Dicer pathway leads to an increase in CFS expression upon induction of replication stress and to an accumulation of 53BP1 nuclear bodies, indicating transmission of replication-associated damage...
July 8, 2019: Oncotarget
Laura Kasak, Margus Punab, Liina Nagirnaja, Marina Grigorova, Ave Minajeva, Alexandra M Lopes, Anna Maria Punab, Kenneth I Aston, Filipa Carvalho, Eve Laasik, Lee B Smith, Donald F Conrad, Maris Laan
Infertility affects around 7% of men worldwide. Idiopathic non-obstructive azoospermia (NOA) is defined as the absence of spermatozoa in the ejaculate due to failed spermatogenesis. There is a high probability that NOA is caused by rare genetic defects. In this study, whole-exome sequencing (WES) was applied to two Estonian brothers diagnosed with NOA and Sertoli cell-only syndrome (SCOS). Compound heterozygous loss-of-function (LoF) variants in FANCM (Fanconi anemia complementation group M) were detected as the most likely cause for their condition...
August 2, 2018: American Journal of Human Genetics
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...
January 2018: 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
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