keyword
https://read.qxmd.com/read/37563658/fance-deficiency-inhibits-primordial-germ-cell-proliferation-associated-with-transcription-replication-conflicts-accumulate-and-dna-repair-defects
#1
JOURNAL ARTICLE
Zhixian Zhou, Huan Yin, Suye Suye, Zhen Ren, Lei Yan, Liye Shi, Chun Fu
Fanconi anemia (FA) gene mutations are critical components in the genetic etiology of premature ovarian insufficiency (POI). Fance-/- mice detected meiotic arrest of primordial germ cells (PGCs) as early as embryonic day (E) 13.5 and exhibited decreased ovarian reserve after birth. However, the mechanism of Fance defect leading to dysgenesis of PGCs is unclear. We aimed to explore the effect of Fance defects on mitotic proliferation of PGCs. Combined with transcriptomic sequencing and validation, we examined the effect of Fance defects on cell cycle, transcription-replication conflicts (TRCs), and multiple DNA repair pathways in PGCs during active DNA replication at E11...
August 10, 2023: Journal of Ovarian Research
https://read.qxmd.com/read/36543851/fancd2-promotes-mitotic-rescue-from-transcription-mediated-replication-stress-in-setx-deficient-cancer-cells
#2
JOURNAL ARTICLE
Maha Said, Viviana Barra, Elisa Balzano, Ibtissam Talhaoui, Franca Pelliccia, Simona Giunta, Valeria Naim
Replication stress (RS) is a leading cause of genome instability and cancer development. A substantial source of endogenous RS originates from the encounter between the transcription and replication machineries operating on the same DNA template. This occurs predominantly under specific contexts, such as oncogene activation, metabolic stress, or a deficiency in proteins that specifically act to prevent or resolve those transcription-replication conflicts (TRCs). One such protein is Senataxin (SETX), an RNA:DNA helicase involved in resolution of TRCs and R-loops...
December 21, 2022: Communications Biology
https://read.qxmd.com/read/35595243/conserved-function-of-drosophila-fancd2-monoubiquitination-in-response-to-double-strand-dna-breaks
#3
JOURNAL ARTICLE
Delisa E Clay, Erin A Jezuit, Ruth A Montague, Donald T Fox
Fanconi Anemia (FA) genes play key roles in metazoan DNA damage responses, and human FA mutations cause numerous disease phenotypes. In human cells, activating monoubiquitination of the FA protein Fancd2 occurs following diverse DNA damage stimuli. Monoubiquitinated Fancd2 forms nuclear foci to recruit additional repair factors. Fancd2 animal models to date have focused on molecular nulls or whole gene knockdown, leaving the specific in vivo role of monoubiquitination unclear. Using a point mutant in a conserved residue, we recently linked Drosophila Fancd2 monoubiquitination to a mitosis-specific DNA double-strand break (DSB) response...
May 20, 2022: G3: Genes—Genomes—Genetics
https://read.qxmd.com/read/35099000/single-cell-transcription-profiles-in-bloom-syndrome-patients-link-blm-deficiency-with-altered-condensin-complex-expression-signatures
#4
JOURNAL ARTICLE
Ipek Ilgin Gönenc, Alexander Wolff, Julia Schmidt, Arne Zibat, Christian Müller, Lukas Cyganek, Loukas Argyriou, Markus Räschle, Gökhan Yigit, Bernd Wollnik
Bloom syndrome (BS) is an autosomal recessive disease clinically characterized by primary microcephaly, growth deficiency, immunodeficiency, and predisposition to cancer. It is mainly caused by biallelic loss-of-function mutations in the BLM gene, which encodes the BLM helicase, acting in DNA replication and repair processes. Here, we describe the gene expression profiles of three BS fibroblast cell lines harboring causative, biallelic truncating mutations obtained by single-cell (sc) transcriptome analysis...
January 31, 2022: Human Molecular Genetics
https://read.qxmd.com/read/34804941/mitotic-errors-promote-genomic-instability-and-leukemia-in-a-novel-mouse-model-of-fanconi-anemia
#5
JOURNAL ARTICLE
Donna M Edwards, Dana K Mitchell, Zahi Abdul-Sater, Ka-Kui Chan, Zejin Sun, Aditya Sheth, Ying He, Li Jiang, Jin Yuan, Richa Sharma, Magdalena Czader, Pei-Ju Chin, Yie Liu, Guillermo de Cárcer, Grzegorz Nalepa, Hal E Broxmeyer, D Wade Clapp, Elizabeth A Sierra Potchanant
Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis in vivo , the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in Fancc-/- mice by introducing heterozygosity of the key spindle assembly checkpoint regulator Mad2 ...
2021: Frontiers in Oncology
https://read.qxmd.com/read/34700968/tumor-treating-fields-synergistically-enhances-cell-death-in-non-small-cell-lung-and-pancreatic-cancer-cells-treated-with-the-combination-of-radiation-and-chemo-agents-that-interfere-with-dna-replication-fork-stability
#6
JOURNAL ARTICLE
N K Karanam, M D Story
PURPOSE/OBJECTIVE(S): TTFields is a novel non-invasive physical modality of cancer therapy which was initially thought to interfere with cancer cell mitosis to induce cell death. Genomics and proteomic results suggested the additional mechanisms of action underlying TTFields induced cell death as increased DNA replication stress and DNA damage while decreasing DNA repair through the downregulation of Fanconi's Anemia (FA) pathway genes, chromosome maintenance genes and others. The current study focused on exploiting the conditional vulnerabilities caused by TTFields exposure to test novel combination therapies that target DNA replication fork stability combined with radiation...
November 1, 2021: International Journal of Radiation Oncology, Biology, Physics
https://read.qxmd.com/read/34613334/persistent-dna-damage-signaling-and-dna-polymerase-theta-promote-broken-chromosome-segregation
#7
JOURNAL ARTICLE
Delisa E Clay, Heidi S Bretscher, Erin A Jezuit, Korie B Bush, Donald T Fox
Cycling cells must respond to DNA double-strand breaks (DSBs) to avoid genome instability. Missegregation of chromosomes with DSBs during mitosis results in micronuclei, aberrant structures linked to disease. How cells respond to DSBs during mitosis is incompletely understood. We previously showed that Drosophilamelanogaster papillar cells lack DSB checkpoints (as observed in many cancer cells). Here, we show that papillar cells still recruit early acting repair machinery (Mre11 and RPA3) and the Fanconi anemia (FA) protein Fancd2 to DSBs...
December 6, 2021: Journal of Cell Biology
https://read.qxmd.com/read/34058059/sik2-kinase-synthetic-lethality-is-driven-by-spindle-assembly-defects-in-fanca-deficient-cells
#8
JOURNAL ARTICLE
Ka-Kui Chan, Zahi Abdul-Sater, Aditya Sheth, Dana K Mitchell, Richa Sharma, Donna M Edwards, Ying He, Grzegorz Nalepa, Steven D Rhodes, D Wade Clapp, Elizabeth A Sierra Potchanant
The Fanconi anemia (FA) pathway safeguards genomic stability through cell cycle regulation and DNA damage repair. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established, but their function in mitosis is incompletely understood. Here we performed a kinome-wide synthetic lethality screen in FANCA-/- fibroblasts, which revealed multiple mitotic kinases as necessary for survival of FANCA-deficient cells. Among these kinases, we identified the depletion of the centrosome kinase SIK2 as synthetic lethal upon loss of FANCA...
May 31, 2021: Molecular Oncology
https://read.qxmd.com/read/32466131/the-fanc-brca-pathway-releases-replication-blockades-by-eliminating-dna-interstrand-cross-links
#9
REVIEW
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
https://read.qxmd.com/read/31707040/tumor-treating-fields-cause-replication-stress-and-interfere-with-dna-replication-fork-maintenance-implications-for-cancer-therapy
#10
JOURNAL ARTICLE
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
https://read.qxmd.com/read/31320994/dicer-prevents-genome-instability-in-response-to-replication-stress
#11
JOURNAL ARTICLE
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
https://read.qxmd.com/read/30075111/bi-allelic-recessive-loss-of-function-variants-in-fancm-cause-non-obstructive-azoospermia
#12
JOURNAL ARTICLE
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
https://read.qxmd.com/read/29125603/cell-cycle-arrest-through-indirect-transcriptional-repression-by-p53-i-have-a-dream
#13
REVIEW
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
https://read.qxmd.com/read/27834954/strong-antitumor-synergy-between-dna-crosslinking-and-hsp90-inhibition-causes-massive-premitotic-dna-fragmentation-in-ovarian-cancer-cells
#14
JOURNAL ARTICLE
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
https://read.qxmd.com/read/27270041/proliferation-of-double-strand-break-resistant-polyploid-cells-requires-drosophila-fancd2
#15
JOURNAL ARTICLE
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
https://read.qxmd.com/read/27193269/1-2-3-4-diepoxybutane-induces-multipolar-mitosis-in-cultured-human-lymphocytes
#16
JOURNAL ARTICLE
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
https://read.qxmd.com/read/26466335/the-fanconi-anemia-c-protein-binds-to-and-regulates-stathmin-1-phosphorylation
#17
JOURNAL ARTICLE
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
https://read.qxmd.com/read/26385365/fanconi-anemia-cells-with-unrepaired-dna-damage-activate-components-of-the-checkpoint-recovery-process
#18
JOURNAL ARTICLE
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
https://read.qxmd.com/read/26366677/fanca-safeguards-interphase-and-mitosis-during-hematopoiesis-in-vivo
#19
JOURNAL ARTICLE
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
https://read.qxmd.com/read/25881042/cell-cycle-regulation-of-human-dna-repair-and-chromatin-remodeling-genes
#20
JOURNAL ARTICLE
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: www.dnarepairgenes.com. 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
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