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https://www.readbyqxmd.com/read/27932447/unloading-of-homologous-recombination-factors-is-required-for-restoring-double-stranded-dna-at-damage-repair-loci
#1
Yulia Vasianovich, Veronika Altmannova, Oleksii Kotenko, Matthew D Newton, Lumir Krejci, Svetlana Makovets
Cells use homology-dependent DNA repair to mend chromosome breaks and restore broken replication forks, thereby ensuring genome stability and cell survival. DNA break repair via homology-based mechanisms involves nuclease-dependent DNA end resection, which generates long tracts of single-stranded DNA required for checkpoint activation and loading of homologous recombination proteins Rad52/51/55/57. While recruitment of the homologous recombination machinery is well characterized, it is not known how its presence at repair loci is coordinated with downstream re-synthesis of resected DNA We show that Rad51 inhibits recruitment of proliferating cell nuclear antigen (PCNA), the platform for assembly of the DNA replication machinery, and that unloading of Rad51 by Srs2 helicase is required for efficient PCNA loading and restoration of resected DNA As a result, srs2Δ mutants are deficient in DNA repair correlating with extensive DNA processing, but this defect in srs2Δ mutants can be suppressed by inactivation of the resection nuclease Exo1...
December 8, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27932446/topoisomerase-i-mediated-cleavage-at-unrepaired-ribonucleotides-generates-dna-double-strand-breaks
#2
Shar-Yin N Huang, Jessica S Williams, Mercedes E Arana, Thomas A Kunkel, Yves Pommier
Ribonuclease activity of topoisomerase I (Top1) causes DNA nicks bearing 2',3'-cyclic phosphates at ribonucleotide sites. Here, we provide genetic and biochemical evidence that DNA double-strand breaks (DSBs) can be directly generated by Top1 at sites of genomic ribonucleotides. We show that RNase H2-deficient yeast cells displayed elevated frequency of Rad52 foci, inactivation of RNase H2 and RAD52 led to synthetic lethality, and combined loss of RNase H2 and RAD51 induced slow growth and replication stress...
December 8, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27924011/roles-for-aprin-pds5b-in-homologous-recombination-and-in-ovarian-cancer-prediction
#3
Anthony M Couturier, Hubert Fleury, Anne-Marie Patenaude, Victoria L Bentley, Amélie Rodrigue, Yan Coulombe, Joshi Niraj, Joris Pauty, Jason N Berman, Graham Dellaire, Javier M Di Noia, Anne-Marie Mes-Masson, Jean-Yves Masson
APRIN (PDS5 cohesin associated factor B) interacts with both the cohesin complex and the BRCA2 tumor suppressor. How APRIN influences cohesion and DNA repair processes is not well understood. Here, we show that APRIN is recruited to DNA damage sites. We find that APRIN interacts directly with RAD51, PALB2 and BRCA2. APRIN stimulates RAD51-mediated DNA strand invasion. APRIN also binds DNA with an affinity for D-loop structures and single-strand (ss) DNA. APRIN is a new homologous recombination (HR) mediator as it counteracts the RPA inhibitory effect on RAD51 loading to ssDNA...
October 24, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27924006/the-homologous-recombination-protein-rad51d-protects-the-genome-from-large-deletions
#4
Wade A Reh, Rodney S Nairn, Megan P Lowery, Karen M Vasquez
Homologous recombination (HR) is a DNA double-strand break (DSB) repair pathway that protects the genome from chromosomal instability. RAD51 mediator proteins (i.e. paralogs) are critical for efficient HR in mammalian cells. However, how HR-deficient cells process DSBs is not clear. Here, we utilized a loss-of-function HR-reporter substrate to simultaneously monitor HR-mediated gene conversion and non-conservative mutation events. The assay is designed around a heteroallelic duplication of the Aprt gene at its endogenous locus in isogenic Chinese hamster ovary cell lines...
December 6, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27923995/homologous-recombination-in-budding-yeast-expressing-the-human-rad52-gene-reveals-a-rad51-independent-mechanism-of-conservative-double-strand-break-repair
#5
Glenn M Manthey, Alissa D Clear, Lauren C Liddell, Maria C Negritto, Adam M Bailis
RAD52 is a homologous recombination (HR) protein that is conserved from bacteriophage to humans. Simultaneously attenuating expression of both the RAD52 gene, and the HR and tumor suppressor gene, BRCA2, in human cells synergistically reduces HR - indicating that RAD52 and BRCA2 control independent mechanisms of HR. We have expressed the human RAD52 gene (HsRAD52) in budding yeast strains lacking the endogenous RAD52 gene and found that HsRAD52 supports repair of DNA double-strand breaks (DSB) by a mechanism of HR that conserves genome structure...
December 6, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27918542/the-role-of-break-induced-replication-in-large-scale-expansions-of-cag-n-ctg-n-repeats
#6
Jane C Kim, Samantha T Harris, Teresa Dinter, Kartik A Shah, Sergei M Mirkin
Expansions of (CAG)n/(CTG)n trinucleotide repeats are responsible for over a dozen neuromuscular and neurodegenerative disorders. Large-scale expansions are commonly observed in human pedigrees and may be explained by iterative small-scale events such as strand slippage during replication or repair DNA synthesis. Alternatively, a distinct mechanism may lead to a large-scale repeat expansion as a single step. To distinguish between these possibilities, we developed a novel experimental system specifically tuned to analyze large-scale expansions of (CAG)n/(CTG)n repeats in Saccharomyces cerevisiae...
December 5, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27903895/protein-dynamics-of-human-rpa-and-rad51-on-ssdna-during-assembly-and-disassembly-of-the-rad51-filament
#7
Chu Jian Ma, Bryan Gibb, YoungHo Kwon, Patrick Sung, Eric C Greene
Homologous recombination (HR) is a crucial pathway for double-stranded DNA break (DSB) repair. During the early stages of HR, the newly generated DSB ends are processed to yield long single-stranded DNA (ssDNA) overhangs, which are quickly bound by replication protein A (RPA). RPA is then replaced by the DNA recombinase Rad51, which forms extended helical filaments on the ssDNA. The resulting nucleoprotein filament, known as the presynaptic complex, is responsible for pairing the ssDNA with homologous double-stranded DNA (dsDNA), which serves as the template to guide DSB repair...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27899501/unraveling-fungal-radiation-resistance-regulatory-networks-through-the-genome-wide-transcriptome-and-genetic-analyses-of-cryptococcus-neoformans
#8
Kwang-Woo Jung, Dong-Hoon Yang, Min-Kyu Kim, Ho Seong Seo, Sangyong Lim, Yong-Sun Bahn
The basidiomycetous fungus Cryptococcus neoformans has been known to be highly radiation resistant and has been found in fatal radioactive environments such as the damaged nuclear reactor at Chernobyl. To elucidate the mechanisms underlying the radiation resistance phenotype of C. neoformans, we identified genes affected by gamma radiation through genome-wide transcriptome analysis and characterized their functions. We found that genes involved in DNA damage repair systems were upregulated in response to gamma radiation...
November 29, 2016: MBio
https://www.readbyqxmd.com/read/27895503/methotrexate-induces-dna-damage-and-inhibits-homologous-recombination-repair-in-choriocarcinoma-cells
#9
Lisha Xie, Tiancen Zhao, Jing Cai, You Su, Zehua Wang, Weihong Dong
OBJECTIVE: The objective of this study was to investigate the mechanism of sensitivity to methotrexate (MTX) in human choriocarcinoma cells regarding DNA damage response. METHODS: Two choriocarcinoma cancer cell lines, JAR and JEG-3, were utilized in this study. An MTX-sensitive osteosarcoma cell line MG63, an MTX-resistant epithelial ovarian cancer cell line A2780 and an MTX-resistant cervical adenocarcinoma cell line Hela served as controls. Cell viability assay was carried out to assess MTX sensitivity of cell lines...
2016: OncoTargets and Therapy
https://www.readbyqxmd.com/read/27893463/inhibition-of-the-gas6-axl-pathway-augments-the-efficacy-of-chemotherapies
#10
Mihalis S Kariolis, Yu Rebecca Miao, Anh Diep, Shannon E Nash, Monica M Olcina, Dadi Jiang, Douglas S Jones, Shiven Kapur, Irimpan I Mathews, Albert C Koong, Erinn B Rankin, Jennifer R Cochran, Amato J Giaccia
The AXL receptor and its activating ligand, growth arrest-specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. However, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. Here, we have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6...
November 28, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27892797/nek8-regulates-dna-damage-induced-rad51-foci-formation-and-replication-fork-protection
#11
Antonio Abeyta, Maria Castella, Celine Jacquemont, Toshiyasu Taniguchi
Proteins essential for homologous recombination play a pivotal role in the repair of DNA double strand breaks, DNA inter-strand crosslinks and replication fork stability. Defects in homologous recombination also play a critical role in the development of cancer and the sensitivity of these cancers to chemotherapy. RAD51, an essential factor for homologous recombination and replication fork protection, accumulates and forms immunocytochemically detectable nuclear foci at sites of DNA damage. To identify kinases that may regulate RAD51 localization to sites of DNA damage, we performed a human kinome siRNA library screen, using DNA damage-induced RAD51 foci formation as readout...
November 28, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27884140/phase-ii-clinical-study-of-valproic-acid-plus-cisplatin-and-cetuximab-in-recurrent-and-or-metastatic-squamous-cell-carcinoma-of-head-and-neck-v-chance-trial
#12
Francesco Caponigro, Elena Di Gennaro, Franco Ionna, Francesco Longo, Corrado Aversa, Ettore Pavone, Maria Grazia Maglione, Massimiliano Di Marzo, Paolo Muto, Ernesta Cavalcanti, Antonella Petrillo, Fabio Sandomenico, Piera Maiolino, Roberta D'Aniello, Gerardo Botti, Rossella De Cecio, Nunzia Simona Losito, Stefania Scala, Annamaria Trotta, Andrea Ilaria Zotti, Francesca Bruzzese, Antonio Daponte, Ester Calogero, Massimo Montano, Monica Pontone, Gianfranco De Feo, Francesco Perri, Alfredo Budillon
BACKGROUND: Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and the combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage. Thus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone deacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal Growth Factor Receptor (anti-EGFR) compounds...
November 25, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27869555/the-influence-of-the-ctip-polymorphism-q418p-on-homologous-recombination-and-predisposition-to-radiation-induced-tumorigenesis-mainly-raml-in-mice
#13
Agata Patel, Jennifer Anderson, Daniela Kraft, Rosemary Finnon, Paul Finnon, Cheryl L Scudamore, Grainne Manning, Robert Bulman, Natalie Brown, Simon Bouffler, Peter O'Neill, Christophe Badie
Exposure to ionizing radiation increases the incidence of acute myeloid leukemia (AML), which has been diagnosed in Japanese atomic bombing survivors, as well as patients treated with radiotherapy. The genetic basis for susceptibility to radiation-induced AML is not well characterized. We previously identified a candidate murine gene for susceptibility to radiation-induced AML (rAML): C-terminal binding protein (CTBP)-interacting protein (CTIP)/retinoblastoma binding protein 8 (RBBP8). This gene is essential for embryonic development, double-strand break (DSB) resection in homologous recombination (HR) and tumor suppression...
November 21, 2016: Radiation Research
https://www.readbyqxmd.com/read/27869163/wwox-brca1-interaction-role-in-dna-repair-pathway-choice
#14
M S Schrock, B Batar, J Lee, T Druck, B Ferguson, J H Cho, K Akakpo, H Hagrass, N A Heerema, F Xia, J D Parvin, C M Aldaz, K Huebner
In this study, loss of expression of the fragile site-encoded Wwox protein was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types, and reduced Wwox protein expression can be detected early during cancer development. We found that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox-knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs)...
November 21, 2016: Oncogene
https://www.readbyqxmd.com/read/27867009/a-polar-and-nucleotide-dependent-mechanism-of-action-for-rad51-paralogs-in-rad51-filament-remodeling
#15
Martin R G Taylor, Mário Špírek, Chu Jian Ma, Raffaella Carzaniga, Tohru Takaki, Lucy M Collinson, Eric C Greene, Lumir Krejci, Simon J Boulton
Central to homologous recombination in eukaryotes is the RAD51 recombinase, which forms helical nucleoprotein filaments on single-stranded DNA (ssDNA) and catalyzes strand invasion with homologous duplex DNA. Various regulatory proteins assist this reaction including the RAD51 paralogs. We recently discovered that a RAD51 paralog complex from C. elegans, RFS-1/RIP-1, functions predominantly downstream of filament assembly by binding and remodeling RAD-51-ssDNA filaments to a conformation more proficient for strand exchange...
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27857978/wrnip1-a-new-guardian-of-genome-integrity-at-stalled-replication-forks
#16
Giuseppe Leuzzi, Veronica Marabitti, Pietro Pichierri, Annapaola Franchitto
Failure to protect and/or restart stalled replication forks contributes to genomic instability. Radiation-sensitive 51 (RAD51) recombinase defends stalled forks from nucleolytic attack, which otherwise can threaten their integrity. Recently, we have uncovered a novel and key function of Werner helicase interacting protein 1 (WRNIP1) as a fork-protective factor working in conjunction with RAD51 in response to replication stress.
2016: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/27849606/multiple-mechanisms-contribute-to-double-strand-break-repair-at-rereplication-forks-in-drosophila-follicle-cells
#17
Jessica L Alexander, Kelly Beagan, Terry L Orr-Weaver, Mitch McVey
Rereplication generates double-strand breaks (DSBs) at sites of fork collisions and causes genomic damage, including repeat instability and chromosomal aberrations. However, the primary mechanism used to repair rereplication DSBs varies across different experimental systems. In Drosophila follicle cells, developmentally regulated rereplication is used to amplify six genomic regions, two of which contain genes encoding eggshell proteins. We have exploited this system to test the roles of several DSB repair pathways during rereplication, using fork progression as a readout for DSB repair efficiency...
November 29, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27830107/congenital-mirror-movements-due-to-rad51-cosegregation-with-a-nonsense-mutation-in-a-norwegian-pedigree-and-review-of-the-literature
#18
Oriane Trouillard, Jeanette Koht, Thorsten Gerstner, Siri Moland, Christel Depienne, Isabelle Dusart, Aurélie Méneret, Marta Ruiz, Caroline Dubacq, Emmanuel Roze
BACKGROUND: Autosomal dominant congenital mirror movements (CMM) is a neurodevelopmental disorder characterized by early onset involuntary movements of one side of the body that mirror intentional movements on the contralateral side; these persist throughout life in the absence of other neurological symptoms. The main culprit genes responsible for this condition are RAD51 and DCC. This condition has only been reported in a few families, and the molecular mechanisms linking RAD51 mutations and mirror movements (MM) are poorly understood...
2016: Tremor and Other Hyperkinetic Movements
https://www.readbyqxmd.com/read/27829157/two-distinct-pathways-support-gene-correction-by-single-stranded-donors-at-dna-nicks
#19
Luther Davis, Nancy Maizels
Nicks are the most common form of DNA damage. The mechanisms of their repair are fundamental to genomic stability and of practical importance for genome engineering. We define two pathways that support homology-directed repair by single-stranded DNA donors. One depends upon annealing-driven strand synthesis and acts at both nicks and double-strand breaks. The other depends upon annealing-driven heteroduplex correction and acts at nicks. Homology-directed repair via these pathways, as well as mutagenic end joining, are inhibited by RAD51 at nicks but largely independent of RAD51 at double-strand breaks...
November 8, 2016: Cell Reports
https://www.readbyqxmd.com/read/27821478/mcl-1-depletion-impairs-dna-dsb-repair-and-re-initiation-of-stalled-dna-replication-forks
#20
Abid R Mattoo, Raj K Pandita, Sharmistha Chakraborty, Vijaya Charaka, Kalpana Mujoo, Clayton R Hunt, Tej K Pandita
Myeloid cell leukemia-1 : MCL-1) is a pro-survival BCL-2 protein family member highly expressed in hematopoietic stem cells (HSCs) and regulated by growth factor signals that manifest anti-apoptotic activity. Here we report that depletion of MCL-1, but not its isoform MCL1S, increases genomic instability and cell sensitivity to ionizing radiation (IR) induced death. MCL-1 association with genomic DNA increased post-irradiation and it co-localized with 53BP1 in foci. Post-irradiation, MCL-1 depleted cells exhibited decreased γ-H2AX foci, decreased phosphorylation of ATR and higher levels of residual 53BP1 and RIF1 foci, suggesting DNA DSB repair by homologous recombination (HR) was compromised...
November 7, 2016: Molecular and Cellular Biology
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