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https://www.readbyqxmd.com/read/29162625/sgs1-binding-to-rad51-stimulates-homology-directed-dna-repair-in-saccharomyces-cerevisiae
#1
Lillian Campos-Doerfler, Salahuddin Syed, Kristina H Schmidt
Accurate repair of DNA breaks is essential for maintaining genome integrity and cellular fitness. Sgs1, the sole member of the RecQ family of DNA helicases in Saccharomyces cerevisiae, is important for both early and late stages of homology-dependent repair. Its large number of physical and genetic interactions with DNA recombination, repair and replication factors has established Sgs1 as a key player in the maintenance of genome integrity. To determine the significance of Sgs1 binding to the strand exchange factor Rad51 we have identified a single amino acid change C-terminal of the helicase core of Sgs1 that disrupts Rad51 binding...
November 21, 2017: Genetics
https://www.readbyqxmd.com/read/29158291/rad51c-xrcc3-facilitates-mitochondrial-dna-replication-and-maintains-integrity-of-the-mitochondrial-genome
#2
Anup Mishra, Sneha Saxena, Anjali Kaushal, Ganesh Nagaraju
Mechanisms underlying mitochondrial genome maintenance have recently gained wide attention as mutations in mitochondrial DNA (mtDNA) lead to inherited muscular and neurological diseases which are linked to aging. It has been previously reported that human RAD51, RAD51C and XRCC3 localize to mitochondria upon oxidative stress and are required for the maintenance of mtDNA stability. Since RAD51 and RAD51 paralogs are spontaneously imported into mitochondria, their precise role in mtDNA maintenance during unperturbed conditions remains elusive...
November 20, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29156796/downregulation-of-dna-repair-proteins-and-increased-dna-damage-in-hypoxic-colon-cancer-cells-is-a-therapeutically-exploitable-vulnerability
#3
Jennifer M J Jongen, Lizet M van der Waals, Kari Trumpi, Jamila Laoukili, Niek A Peters, Susanne J Schenning-van Schelven, Klaas M Govaert, Inne H M Borel Rinkes, Onno Kranenburg
Surgical removal of colorectal cancer (CRC) liver metastases generates areas of tissue hypoxia. Hypoxia imposes a stem-like phenotype on residual tumor cells and promotes tumor recurrence. Moreover, in primary CRC, gene expression signatures reflecting hypoxia and a stem-like phenotype are highly expressed in the aggressive Consensus Molecular Subtype 4 (CMS4). Therapeutic strategies eliminating hypoxic stem-like cells may limit recurrence following resection of primary tumors or metastases. Here we show that expression of DNA repair genes is strongly suppressed in CMS4 and inversely correlated with hypoxia-inducible factor-1 alpha (HIF1α) and HIF-2α co-expression signatures...
October 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29156644/akt1-stimulates-homologous-recombination-repair-of-dna-double-strand-breaks-in-a-rad51-dependent-manner
#4
Katharina Mueck, Simone Rebholz, Mozhgan Dehghan Harati, H Peter Rodemann, Mahmoud Toulany
Akt1 is known to promote non-homologous end-joining (NHEJ)-mediated DNA double-strand break (DSB) repair by stimulation of DNA-PKcs. In the present study, we investigated the effect of Akt1 on homologous recombination (HR)-dependent repair of radiation-induced DSBs in non-small cell lung cancer (NSCLC) cells A549 and H460. Akt1-knockdown (Akt1-KD) significantly reduced Rad51 protein level, Rad51 foci formation and its colocalization with γH2AX foci after irradiation. Moreover, Akt1-KD decreased clonogenicity after treatment with Mitomycin C and HR repair, as tested by an HR-reporter assay...
November 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29153834/precise-editing-at-dna-replication-forks-enables-multiplex-genome-engineering-in-eukaryotes
#5
Edward M Barbieri, Paul Muir, Benjamin O Akhuetie-Oni, Christopher M Yellman, Farren J Isaacs
We describe a multiplex genome engineering technology in Saccharomyces cerevisiae based on annealing synthetic oligonucleotides at the lagging strand of DNA replication. The mechanism is independent of Rad51-directed homologous recombination and avoids the creation of double-strand DNA breaks, enabling precise chromosome modifications at single base-pair resolution with an efficiency of >40%, without unintended mutagenic changes at the targeted genetic loci. We observed the simultaneous incorporation of up to 12 oligonucleotides with as many as 60 targeted mutations in one transformation...
November 15, 2017: Cell
https://www.readbyqxmd.com/read/29152062/rapamycin-sensitizes-cancer-cells-to-growth-inhibition-by-the-parp-inhibitor-olaparib
#6
Atsushi Osoegawa, Joell J Gills, Shigeru Kawabata, Phillip A Dennis
Poly (ADP-ribose) polymerase inhibitors (PARPi) have been developed and tested in a context of combining it with double-stranded (ds) DNA repair defects or inhibitors, as PARP inhibitor impairs single-stranded (ss) DNA break repair, resulting in the activation of the dsDNA break repair machinery. Rapamycin has been widely prescribed for more than a decade and recent studies have revealed that it may inhibit dsDNA break repair. The combination of the PARP inhibitor olaparib and rapamycin synergistically inhibited cell proliferation in non-small cell lung cancer (NSCLC) cells, and even in triple negative breast cancer (TNBC) cells with BRCA1 mutations...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29151191/silica-nanoparticle-exposure-inducing-granulosa-cell-apoptosis-and-follicular-atresia-in-female-balb-c-mice
#7
Jianhui Liu, Man Yang, Li Jing, Lihua Ren, Jialiu Wei, Jin Zhang, Feng Zhang, Junchao Duan, Xianqing Zhou, Zhiwei Sun
Given that the effects of ultrafine fractions (< 0.1 μm) on reproductive diseases are gaining attention, this study aimed to explore the influence of silica nanoparticle (SiNP)-induced female reproductive dysfunction. In this study, 80 female mice were randomly divided into four groups including a control group and three concentrations of SiNP groups (7, 21, 35 mg/kg). Mice were exposed to the vehicle control and silica nanoparticles by tracheal perfusion every 3 days a total of five times in 15 days...
November 19, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/29145667/planarians-customize-their-stem-cell-responses-following-genotoxic-stress-as-a-function-of-exposure-time-and-regenerative-state
#8
An-Sofie Stevens, Annelies Wouters, Jan-Pieter Ploem, Nicky Pirotte, Andromeda Van Roten, Maxime Willems, Niels Hellings, Carmen Franken, Gudrun Koppen, Tom Artois, Michelle Plusquin, Karen Smeets
Aiming to in vivo characterise the responses of pluripotent stem cells and regenerative tissues to carcinogenic stress, we employed the highly regenerative organism Schmidtea mediterranea. Its broad regenerative capacities are attributable to a large pool of pluripotent stem cells, which are considered key players in the lower vulnerability towards chemically-induced carcinogenesis observed in regenerative organisms. S. mediterranea is, therefore, an ideal model to study pluripotent stem cell responses with stem cells residing in their natural environment...
November 14, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29138572/current-status-of-poly-adp-ribose-polymerase-inhibitors-and-future-directions
#9
REVIEW
Akihiro Ohmoto, Shinichi Yachida
Inhibitors of poly(ADP-ribose) polymerases (PARPs), which play a key role in DNA damage/repair pathways, have been developed as antitumor agents based on the concept of synthetic lethality. Synthetic lethality is the idea that cell death would be efficiently induced by simultaneous loss of function of plural key molecules, for example, by exposing tumor cells with inactivating gene mutation of BRCA-mediated DNA repair to chemically induced inhibition of PARPs. Indeed, three PARP inhibitors, olaparib, rucaparib and niraparib have already been approved in the US or Europe, mainly for the treatment of BRCA-mutant ovarian cancer...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29137223/hormone-induced-dna-damage-response-and-repair-mediated-by-cyclin-d1-in-breast-and-prostate-cancer
#10
REVIEW
Gabriele Di Sante, Agnese Di Rocco, Claudia Pupo, Mathew C Casimiro, Richard G Pestell
Cell cycle control proteins govern events that leads to the production of two identical daughter cells. Distinct sequential temporal phases, Gap 1 (G1), Gap 0 (G0), Synthesis (S), Gap 2 (G2) and Mitosis (M) are negotiated through a series of check points during which the favorability of the local cellular environment is assessed, prior to replicating DNA [1]. Cyclin D1 has been characterized as a key regulatory subunit of the holoenzyme that promotes the G1/S-phase transition through phosphorylating the pRB protein...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29133916/brca2-antagonizes-classical-and-alternative-nonhomologous-end-joining-to-prevent-gross-genomic-instability
#11
Jinhua Han, Chunyan Ruan, Michael S Y Huen, Jiadong Wang, Anyong Xie, Chun Fu, Ting Liu, Jun Huang
BRCA2-deficient cells exhibit gross genomic instability, but the underlying mechanisms are not fully understood. Here we report that inactivation of BRCA2 but not RAD51 destabilizes RPA-coated single-stranded DNA (ssDNA) structures at resected DNA double-strand breaks (DSBs) and greatly enhances the frequency of nuclear fragmentation following cell exposure to DNA damage. Importantly, these BRCA2-associated deficits are fueled by the aberrant activation of classical (c)- and alternative (alt)- nonhomologous end-joining (NHEJ), and rely on the well-defined DNA damage signaling pathway involving the pro-c-NHEJ factor 53BP1 and its downstream effector RIF1...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29129974/screening-of-pesticides-with-the-potential-of-inducing-dsb-and-successive-recombinational-repair
#12
Karen Suárez-Larios, Ana-María Salazar-Martínez, Regina Montero-Montoya
A study was realized to ascertain whether eight selected pesticides would induce double strand breaks (DSB) in lymphocyte cultures and whether this damage would induce greater levels of proteins Rad51 participating in homologous recombination or of p-Ku80 participating in nonhomologous end joining. Only five pesticides were found to induce DSB of which only glyphosate and paraoxon induced a significant increase of p-Ku80 protein, indicating that nonhomologous end joining recombinational DNA repair system would be activated...
2017: Journal of Toxicology
https://www.readbyqxmd.com/read/29128690/transcriptome-based-biological-dosimetry-of-gamma-radiation-in-arabidopsis-using-dna-damage-response-genes
#13
Tae Ho Ryu, Jin Kyu Kim, Jeong-Il Kim, Jin-Hong Kim
Plants are used as representative reference biota for the biological assessment of environmental risks such as ionizing radiation due to their immobility. This study proposed a faster, more economical, and more effective method than conventional cytogenetic methods for the biological dosimetry of ionizing radiation in plants (phytodosimetry). We compared various dose-response curves for the radiation-induced DNA damage response (DDR) in Arabidopsis thaliana after relatively "low-dose" gamma irradiation (3, 6, 12, 24, and 48 Gy) below tens of Gy using comet (or single-cell gel electrophoresis), gamma-H2AX, and transcriptomic assays of seven DDR genes (AGO2, BRCA1, GRG, PARP1, RAD17, RAD51, and RPA1E) using quantitative real time PCR...
November 9, 2017: Journal of Environmental Radioactivity
https://www.readbyqxmd.com/read/29126163/identification-of-novel-cancer-biomarkers-of-prognostic-value-using-specific-gene-regulatory-networks-grn-a-novel-role-of-rad51ap1-for-ovarian-and-lung-cancers
#14
Dimple Chudasama, Valeria Bo, Marcia Hall, Vladimir Anikin, Jeyarooban Jeyaneethi, Jane Gregory, George Pados, Allan Tucker, Amanda Harvey, Ryan Pink, Emmanouil Karteris
To date, microarray analyses have led to the discovery of numerous individual "molecular signatures" associated with specific cancers. However, there are serious limitations for the adoption of these multi-gene signatures in the clinical environment for diagnostic or prognostic testing as studies with more power need to be carried out. This may involve larger richer cohorts and more advanced analyses.In this study, we conduct analyses -based on GRN- to reveal distinct and common biomarkers across cancer types...
November 8, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29116362/homologous-recombination-mediated-repair-of-dna-double-strand-breaks-operates-in-mammalian-mitochondria
#15
Sumedha Dahal, Shubham Dubey, Sathees C Raghavan
Mitochondrial DNA is frequently exposed to oxidative damage, as compared to nuclear DNA. Previously, we have shown that while microhomology-mediated end joining can account for DNA deletions in mitochondria, classical nonhomologous DNA end joining, the predominant double-strand break (DSB) repair pathway in nucleus, is undetectable. In the present study, we investigated the presence of homologous recombination (HR) in mitochondria to maintain its genomic integrity. Biochemical studies revealed that HR-mediated repair of DSBs is more efficient in the mitochondria of testes as compared to that of brain, kidney and spleen...
November 7, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29112893/natural-product-%C3%AE-thujaplicin-inhibits-homologous-recombination-repair-and-sensitizes-cancer-cells-to-radiation-therapy
#16
Lihong Zhang, Yang Peng, Ivan P Uray, Jianfeng Shen, Lulu Wang, Xiangdong Peng, Powel H Brown, Wei Tu, Guang Peng
Investigation of natural products is an attractive strategy to identify novel compounds for cancer prevention and treatment. Numerous studies have shown the efficacy and safety of natural products, and they have been widely used as alternative treatments for a wide range of illnesses, including cancers. However, it remains unknown whether natural products affect homologous recombination (HR)-mediated DNA repair and whether these compounds can be used as sensitizers with minimal toxicity to improve patients' responses to radiation therapy, a mainstay of treatment for many human cancers...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29111564/relationship-between-xpd-rad51-and-apex1-dna-repair-genotypes-and-prostate-cancer-risk-in-the-male-population-of-rio-de-janeiro-brazil
#17
Ana Sheila Cypriano, Gilda Alves, Antonio Augusto Ornellas, José Scheinkman, Renata Almeida, Luciano Scherrer, Claudia Lage
Susceptibility to cancer ensues in individuals carrying malfunctioning DNA repair mechanisms. The impact of Single Nucleotide Polymorphisms (SNPs) in key DNA repair mechanisms on risk for prostate cancer was investigated in this case-control study. Samples consisted of 110 patients with confirmed prostate cancer and 200 unaffected men, from Rio de Janeiro, Brazil. XPD/Lys751Gln (rs13181), APEX1/Asp148Glu (rs1130409), and RAD51/G135C (rs1801320) SNPs were analyzed by PCR-RFLP. Allelic and genotypic frequencies were calculated and compared by Chi-Square test...
November 6, 2017: Genetics and Molecular Biology
https://www.readbyqxmd.com/read/29103969/differentiation-of-human-induced-pluripotent-or-embryonic-stem-cells-decreases-the-dna-damage-repair-by-homologous-recombination
#18
Kalpana Mujoo, Raj K Pandita, Anjana Tiwari, Vijay Charaka, Sharmistha Chakraborty, Dharmendra Kumar Singh, Shashank Hambarde, Walter N Hittelman, Nobuo Horikoshi, Clayton R Hunt, Kum Kum Khanna, Alexander Y Kots, E Brian Butler, Ferid Murad, Tej K Pandita
The nitric oxide (NO)-cyclic GMP pathway contributes to human stem cell differentiation, but NO free radical production can also damage DNA, necessitating a robust DNA damage response (DDR) to ensure cell survival. How the DDR is affected by differentiation is unclear. Differentiation of stem cells, either inducible pluripotent or embryonic derived, increased residual DNA damage as determined by γ-H2AX and 53BP1 foci, with increased S-phase-specific chromosomal aberration after exposure to DNA-damaging agents, suggesting reduced homologous recombination (HR) repair as supported by the observation of decreased HR-related repair factor foci formation (RAD51 and BRCA1)...
November 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29100040/defects-in-recombination-activity-caused-by-somatic-and-germline-mutations-in-the-multimerization-brca2-binding-region-of-human-rad51-protein
#19
Michelle C Silva, Katie E Bryan, Milagros D Morrical, April M Averill, Julie Dragon, Adrian P Wiegmans, Scott W Morrical
The human RAD51 recombinase possesses DNA pairing and strand exchange activities that are essential for the error-free, homology-directed repair of DNA double-strand breaks. The recombination activities of RAD51 are activated upon its assembly into presynaptic filaments on single-stranded DNA at resected DSB ends. Defects in filament assembly caused by mutations in RAD51 or its regulators such as BRCA2 are associated with human cancer. Here we describe two novel RAD51 missense variants located in the multimerization/BRCA2 binding region of RAD51...
December 2017: DNA Repair
https://www.readbyqxmd.com/read/29099268/atm-mediated-mitochondrial-damage-response-triggered-by-nuclear-dna-damage-in-normal-human-lung-fibroblasts
#20
Tsutomu Shimura, Megumi Sasatani, Hidehiko Kawai, Kenji Kamiya, Junya Kobayashi, Kenshi Komatsu, Naoki Kunugita
Ionizing radiation (IR) elevates mitochondrial oxidative phosphorylation (OXPHOS) in response to the energy requirement for DNA damage responses. Reactive oxygen species (ROS) released during mitochondrial OXPHOS may cause oxidative damage to mitochondria in irradiated cells. In this paper, we investigated the association between nuclear DNA damage and mitochondrial damage following IR in normal human lung fibroblasts. In contrast to low-doses of acute single radiation, continuous exposure of chronic radiation or long-term exposure of fractionated radiation (FR) induced persistent Rad51 and γ-H2AX foci at least 24 hours after IR in irradiated cells...
November 3, 2017: Cell Cycle
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