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https://www.readbyqxmd.com/read/27895153/ubiquitylation-of-ku80-by-rnf126-promotes-completion-of-nhej-mediated-dna-repair
#1
Noriko Ishida, Tadashi Nakagawa, Shun-Ichiro Iemura, Akira Yasui, Hiroki Shima, Yasutake Katoh, Yuko Nagasawa, Toru Natsume, Kazuhiko Igarashi, Keiko Nakayama
Repair of damaged DNA is critical for maintenance of genetic information. In eukaryotes, DNA double-strand breaks (DSBs) are recognized by the Ku70-Ku80 heterodimer, which then recruits proteins that mediate repair by nonhomologous end-joining (NHEJ). Prolonged retention of Ku70/80 at DSBs prevents completion of repair, however, with ubiquitylation of Ku80 having been implicated in Ku70/80 dissociation from DNA. Here we identify RNF126 as a ubiquitin ligase that is recruited to DSBs and ubiquitylates Ku80, with UBE2D3 serving as an E2...
November 28, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27875301/an-intrinsically-disordered-aplf-links-ku-dna-pkcs-and-xrcc4-dna-ligase-iv-in-an-extended-flexible-non-homologous-end-joining-complex
#2
Michal Hammel, Yaping Yu, Sarvan Kumar Radhakrishnan, Chirayu Chokshi, Miaw-Sheue Tsai, Yoshihiro Matsumoto, Monica Kuzdovich, Soumya G Remesh, Shujuan Fang, Alan E Tomkinson, Susan P Lees-Miller, John A Tainer
DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF) and XRCC4 (X4)-DNA ligase IV (L4). In addition, Ku interacts with accessory factors such as Aprataxin and Polynucleotide kinase/phosphatase-Like Factor (APLF), yet how these factors interact to tether, process and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic...
November 14, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27866150/crispr-cas9-induced-double-strand-break-repair-in-arabidopsis-non-homologous-end-joining-mutants
#3
Hexi Shen, Gary D Strunks, Bart J P M Klemann, Paul J J Hooykaas, Sylvia de Pater
Double-strand breaks (DSBs) are one of the most harmful DNA lesions. Cells utilize two main pathways for DSB repair: homologous recombination (HR) and non-homologous end-joining (NHEJ). NHEJ can be subdivided into the KU-dependent classical NHEJ (c-NHEJ) and the more error-prone KU-independent backup-NHEJ (b-NHEJ) pathways, involving the poly (ADP-ribose) polymerases (PARPs). However, in absence of these factors, cells still seem able to adequately maintain genome integrity, suggesting the presence of other b-NHEJ repair factors or pathways independent from KU and PARPs...
November 18, 2016: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/27849008/ku70-serine-155-mediates-aurora-b-inhibition-and-activation-of-the-dna-damage-response
#4
Victoria L Fell, Elizabeth A Walden, Sarah M Hoffer, Stephanie R Rogers, Amelia S Aitken, Louisa M Salemi, Caroline Schild-Poulter
The Ku heterodimer (Ku70/Ku80) is the central DNA binding component of the classical non-homologous end joining (NHEJ) pathway that repairs DNA double-stranded breaks (DSBs), serving as the scaffold for the formation of the NHEJ complex. Here we show that Ku70 is phosphorylated on Serine 155 in response to DNA damage. Expression of Ku70 bearing a S155 phosphomimetic substitution (Ku70 S155D) in Ku70-deficient mouse embryonic fibroblasts (MEFs) triggered cell cycle arrest at multiple checkpoints and altered expression of several cell cycle regulators in absence of DNA damage...
November 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27830975/deficiency-of-xlf-and-paxx-prevents-dna-double-strand-break-repair-by-non-homologous-end-joining-in-lymphocytes
#5
Putzer J Hung, Bo-Ruei Chen, Rosmy George, Caleb Liberman, Abigail J Morales, Pedro Colon-Ortiz, Jessica K Tyler, Barry P Sleckman, Andrea L Bredemeyer
Non-homologous end joining (NHEJ) is a major DNA double-strand break (DSB) repair pathway that functions in all phases of the cell cycle. NHEJ repairs genotoxic and physiological DSBs, such as those generated by ionizing radiation and during V(D)J recombination at antigen receptor loci, respectively. DNA end joining by NHEJ relies on the core factors Ku70, Ku80, XRCC4, and DNA Ligase IV. Additional proteins also play important roles in NHEJ. The XRCC4-like factor (XLF) participates in NHEJ through its interaction with XRCC4, and XLF deficiency in humans leads to immunodeficiency and increased sensitivity to ionizing radiation...
November 10, 2016: Cell Cycle
https://www.readbyqxmd.com/read/27825805/humanku70-protein-binds-hairpin-rna-and-double-stranded-dna-through-two-different-sites
#6
Andrey N Anisenko, Ekaterina S Knyazhanskaya, Timofey S Zatsepin, Marina B Gottikh
Human protein Ku usually functions in the cell as a complex of two subunits, Ku70 and Ku80. The Ku heterodimer plays a key role in the non-homologous end joining DNA repair pathway by specifically recognizing the DNA ends at the site of the lesion. The binding of the Ku heterodimer to DNA has been well-studied, and its interactions with RNA have been also described. However, Ku70 subunit is known to have independent DNA binding capability, which is less characterized. RNA binding properties of Ku70 have not been yet specially studied...
November 4, 2016: Biochimie
https://www.readbyqxmd.com/read/27803664/herpes-simplex-virus-type1-hsv-1-impairs-dna-repair-in-cortical-neurons
#7
Giovanna De Chiara, Mauro Racaniello, Cristiana Mollinari, Maria Elena Marcocci, Giorgia Aversa, Alessio Cardinale, Anna Giovanetti, Enrico Garaci, Anna Teresa Palamara, Daniela Merlo
Several findings suggest that Herpes simplex virus-1 (HSV-1) infection plays a role in the neurodegenerative processes that characterize Alzheimer's disease (AD), but the underlying mechanisms have yet to be fully elucidated. Here we show that HSV-1 productive infection in cortical neurons causes the accumulation of DNA lesions that include both single (SSBs) and double strand breaks (DSBs), which are reported to be implicated in the neuronal loss observed in neurodegenerative diseases. We demonstrate that HSV-1 downregulates the expression level of Ku80, one of the main components of non-homologous end joining (NHEJ), a major pathway for the repair of DSBs...
2016: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/27798842/synthetic-lethality-between-paxx-and-xlf-in-mammalian-development
#8
Gabriel Balmus, Ana C Barros, Paul W G Wijnhoven, Chloé Lescale, Hélène Lenden Hasse, Katharina Boroviak, Carlos le Sage, Brendan Doe, Anneliese O Speak, Antonella Galli, Matt Jacobsen, Ludovic Deriano, David J Adams, Andrew N Blackford, Stephen P Jackson
PAXX was identified recently as a novel nonhomologous end-joining DNA repair factor in human cells. To characterize its physiological roles, we generated Paxx-deficient mice. Like Xlf(-/-) mice, Paxx(-/-) mice are viable, grow normally, and are fertile but show mild radiosensitivity. Strikingly, while Paxx loss is epistatic with Ku80, Lig4, and Atm deficiency, Paxx/Xlf double-knockout mice display embryonic lethality associated with genomic instability, cell death in the central nervous system, and an almost complete block in lymphogenesis, phenotypes that closely resemble those of Xrcc4(-/-) and Lig4(-/-) mice...
October 1, 2016: Genes & Development
https://www.readbyqxmd.com/read/27746407/cloning-localization-and-focus-formation-at-dna-damage-sites-of-canine-xlf
#9
Manabu Koike, Yasutomo Yutoku, Aki Koike
Understanding the molecular mechanisms of DNA double-strand break (DSB) repair processes, especially nonhomologous DNA-end joining (NHEJ), is critical for developing next-generation radiotherapies and chemotherapeutics for human and animal cancers. The localization, protein-protein interactions and post-translational modifications of core NHEJ factors, such as human Ku70 and Ku80, might play critical roles in controlling NHEJ activity. XRCC4-like factor (XLF) is a core NHEJ factor and plays a key role in the Ku-dependent NHEJ repair process in human cells...
October 14, 2016: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/27721405/eaf2-regulates-dna-repair-through-ku70-ku80-in-the-prostate
#10
J Ai, L E Pascal, L Wei, Y Zang, Y Zhou, X Yu, Y Gong, S Nakajima, J B Nelson, A S Levine, L Lan, Z Wang
Androgens are known to protect prostate cancer cells from DNA damage. Recent studies showed regulation of DNA repair genes by androgen receptor signaling in prostate cancers. ELL-associated factor 2 (EAF2) is an androgen-regulated tumor suppressor and its intracellular localization can be modulated by ultraviolet light, suggesting a potential role for EAF2 in androgen regulation of DNA repair in prostate cancer cells. Here we show that knockdown of EAF2 or its homolog EAF1 sensitized prostate cancer cells to DNA damage and the sensitization did not require p53...
October 10, 2016: Oncogene
https://www.readbyqxmd.com/read/27721000/effects-of-extremely-low-frequency-electromagnetic-field-and-cisplatin-on-mrna-levels-of-some-dna-repair-genes
#11
Fatemeh Sanie-Jahromi, Iraj Saadat, Mostafa Saadat
AIMS: It has been shown that exposure to extremely-low frequency (˂300Hz) oscillating electromagnetic field (EMF) can affect gene expression. The effects of different exposure patterns of 50-Hz EMF and co-treatment of EMF plus cisplatin (CDDP) on mRNA levels of seven genes involved in DNA repair pathways (GADD45A, XRCC1, XRCC4, Ku70, Ku80, DNA-PKcs and LIG4) were evaluated. MAIN METHODS: Two 50-Hz EMF intensities (0.25 and 0.50mT), three exposure patterns (5min field-on/5min field-off, 15min field-on/15min field-off, 30min field-on continuously) and two cell lines (MCF-7 and SH-SY5Y) were used...
October 6, 2016: Life Sciences
https://www.readbyqxmd.com/read/27716483/vcp-p97-extracts-sterically-trapped-ku70-80-rings-from-dna-in-double-strand-break-repair
#12
Johannes van den Boom, Markus Wolf, Lena Weimann, Nina Schulze, Fanghua Li, Farnusch Kaschani, Anne Riemer, Christian Zierhut, Markus Kaiser, George Iliakis, Hironori Funabiki, Hemmo Meyer
During DNA double-strand break (DSB) repair, the ring-shaped Ku70/80 complex becomes trapped on DNA and needs to be actively extracted, but it has remained unclear what provides the required energy. By means of reconstitution of DSB repair on beads, we demonstrate here that DNA-locked Ku rings are released by the AAA-ATPase p97. To achieve this, p97 requires ATP hydrolysis, cooperates with the Ufd1-Npl4 ubiquitin-adaptor complex, and specifically targets Ku80 that is modified by K48-linked ubiquitin chains...
October 6, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27687219/resistance-training-and-redox-homeostasis-correlation-with-age-associated-genomic-changes
#13
Ivan Dimauro, Mattia Scalabrin, Cristina Fantini, Elisa Grazioli, Maria Reyes Beltran Valls, Neri Mercatelli, Attilio Parisi, Stefania Sabatini, Luigi Di Luigi, Daniela Caporossi
Regular physical activity is effective as prevention and treatment for different chronic conditions related to the ageing processes. In fact, a sedentary lifestyle has been linked to a worsening of cellular ageing biomarkers such as telomere length (TL) and/or specific epigenetic changes (e.g. DNA methylation), with increase of the propensity to aging-related diseases and premature death. Extending our previous findings, we aimed to test the hypothesis that 12 weeks of low frequency, moderate intensity, explosive-type resistance training (EMRT) may attenuate age-associated genomic changes...
September 21, 2016: Redox Biology
https://www.readbyqxmd.com/read/27685632/hsa-mir-623-suppresses-tumor-progression-in-human-lung-adenocarcinoma
#14
Shuang Wei, Zun-Yi Zhang, Sheng-Ling Fu, Jun-Gang Xie, Xian-Sheng Liu, Yong-Jian Xu, Jian-Ping Zhao, Wei-Ning Xiong
Our previous study revealed that Ku80 was overexpressed in lung cancer tissues and hsa-miR-623 regulated the Ku80 expression; however, the detailed function of hsa-miR-623 in lung cancer was unclear. We identified that hsa-miR-623 bound to the 3'-UTR of Ku80 mRNA, thus significantly decreasing Ku80 expression in lung adenocarcinoma cells. Hsa-miR-623 was downregulated in lung adenocarcinoma tissues compared with corresponding non-tumorous tissues, and its expression was inversely correlated with Ku80 upregulation...
2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27673354/pomegranate-intake-protects-against-genomic-instability-induced-by-medical-x-rays-in-vivo-in-mice
#15
Sameera Nallanthighal, Amit B Shirode, Julius A Judd, Ramune Reliene
Ionizing radiation (IR) is a well-documented human carcinogen. The increased use of IR in medical procedures has doubled the annual radiation dose and may increase cancer risk. Genomic instability is an intermediate lesion in IR-induced cancer. We examined whether pomegranate extract (PE) suppresses genomic instability induced by x-rays. Mice were treated orally with PE and exposed to an x-ray dose of 2 Gy. PE intake suppressed x-ray-induced DNA double-strand breaks (DSBs) in peripheral blood and chromosomal damage in bone marrow...
September 27, 2016: Nutrition and Cancer
https://www.readbyqxmd.com/read/27644316/cloning-localization-and-focus-formation-at-dna-damage-sites-of-canine-xrcc4
#16
Manabu Koike, Yasutomo Yutoku, Aki Koike
Various chemotherapies and radiation therapies are useful for killing cancer cells mainly by inducing DNA double-strand breaks (DSBs). Uncovering the molecular mechanisms of DSB repair processes is crucial for developing next-generation radiotherapies and chemotherapeutics for human and animal cancers. XRCC4 plays a critical role in Ku-dependent nonhomologous DNA-end joining (NHEJ) in human cells and is one of the core NHEJ factors. The localization of core NHEJ factors, such as human Ku70 and Ku80, might play a crucial role in regulating NHEJ activity...
September 18, 2016: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/27621574/perspectives-on-the-combination-of-radiotherapy-and-targeted-therapy-with-dna-repair-inhibitors-in-the-treatment-of-pancreatic-cancer
#17
REVIEW
Shih-Hung Yang, Ting-Chun Kuo, Hsu Wu, Jhe-Cyuan Guo, Chiun Hsu, Chih-Hung Hsu, Yu-Wen Tien, Kun-Huei Yeh, Ann-Lii Cheng, Sung-Hsin Kuo
Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation (radiosensitization) through inhibition of DNA repair pathways...
August 28, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27593107/analysis-of-relation-between-hypoxia-pet-imaging-and-tissue-based-biomarkers-during-head-and-neck-radiochemotherapy
#18
Martin-Immanuel Bittner, Nicole Wiedenmann, Sabine Bucher, Michael Hentschel, Michael Mix, Gerta Rücker, Wolfgang A Weber, Philipp T Meyer, Martin Werner, Anca-Ligia Grosu, Gian Kayser
BACKGROUND: Tumor hypoxia is associated with poor prognosis and outcome and can be visualized using 18F-MISO-positron emission tomography (PET) imaging. The goal of this study was to evaluate the correlation between biological markers and biological imaging in a group of patients in whom a correlation between biological imaging and outcome has previously been demonstrated. MATERIAL AND METHODS: In a prospective pilot project, 16 patients with locally advanced cancer of the head and neck underwent 18F-MISO-PET scans before and during primary radiochemotherapy in addition to 18F-FDG-PET and computed tomography (CT)...
November 2016: Acta Oncologica
https://www.readbyqxmd.com/read/27537368/the-transcriptional-response-to-dna-double-strand-breaks-in-physcomitrella-patens
#19
Yasuko Kamisugi, John W Whitaker, Andrew C Cuming
The model bryophyte Physcomitrella patens is unique among plants in supporting the generation of mutant alleles by facile homologous recombination-mediated gene targeting (GT). Reasoning that targeted transgene integration occurs through the capture of transforming DNA by the homology-dependent pathway for DNA double-strand break (DNA-DSB) repair, we analysed the genome-wide transcriptomic response to bleomycin-induced DNA damage and generated mutants in candidate DNA repair genes. Massively parallel (Illumina) cDNA sequencing identified potential participants in gene targeting...
2016: PloS One
https://www.readbyqxmd.com/read/27488115/cytosolic-ku70-regulates-bax-mediated-cell-death
#20
Manila Hada, Chitra Subramanian, Phillip C Andrews, Roland P S Kwok
The first known function of Ku70 is as a DNA repair factor in the nucleus. Using neuronal neuroblastoma cells as a model, we have established that cytosolic Ku70 binds to the pro-apoptotic protein Bax in the cytosol and blocks Bax's cell death activity. Ku70-Bax binding is regulated by Ku70 acetylation in that when Ku70 is acetylated Bax dissociates from Ku70, triggering cell death. We propose that Ku70 may act as a survival factor in these cells such that Ku70 depletion triggers Bax-dependent cell death. Here, we addressed two fundamental questions about this model: (1) Does all Bax, which is a cytosolic protein, bind to all cytosolic Ku70? and (2) Is Ku70 a survival factor in cells types other than neuronal neuroblastoma cells? We show here that, in neuronal neuroblastoma cells, only a small fraction of Ku70 binds to a small fraction of Bax; most Bax is monomeric...
October 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
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