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Shubhankar Suman, Santosh Kumar, Prosper N'Gouemo, Kamal Datta
Binge drinking is known to cause damage in critical areas of the brain, including the hippocampus, which is important for relational memory and is reported to be sensitive to alcohol toxicity. However, the roles of DNA double-strand break (DSB) and its repair pathways, homologous recombination (HR), and non-homologous end joining (NHEJ) in alcohol-induced hippocampal injury remain to be elucidated. The purpose of this first study was to assess alcohol-induced DNA DSB and the mechanism by which alcohol affects DSB repair pathways in rat hippocampus...
August 2016: Alcohol
Masakazu Hori, Masanori Someya, Yoshihisa Matsumoto, Kensei Nakata, Mio Kitagawa, Tomokazu Hasegawa, Takaaki Tsuchiya, Yuki Fukushima, Toshio Gocho, Yasushi Sato, Hiroyuki Ohnuma, Junji Kato, Shintaro Sugita, Tadashi Hasegawa, Koh-Ichi Sakata
DNA double-strand break (DSB) is one of the most serious forms of damage induced by ionizing irradiation and is mainly repaired by the non-homologous end joining (NHEJ) repair. Immunohistochemical analysis of proteins involved in NHEJ, such as XRCC4 (X-ray repair cross-complementing protein 4), Ku86 and DNA-PKcs (DNA-dependent protein kinase, catalytic subunits), may be useful for predicting tumor radiosensitivity. We examined 92 patients with esophageal squamous cell carcinoma (ECSS) who were treated by radiotherapy between 1999 and 2008...
June 23, 2016: Medical Molecular Morphology
Julio Castaño, Ana B Herrero, Aldeheid Bursen, Federico González, Rolf Marschalek, Norma C Gutiérrez, Pablo Menendez
The most frequent rearrangement of the human MLL gene fuses MLL to AF4 resulting in high-risk infant B-cell acute lymphoblastic leukemia (B-ALL). MLL fusions are also hallmark oncogenic events in secondary acute myeloid leukemia. They are a direct consequence of mis-repaired DNA double strand breaks (DNA-DSBs) due to defects in the DNA damage response associated with exposure to topoisomerase-II poisons such as etoposide. It has been suggested that MLL fusions render cells susceptible to additional chromosomal damage upon exposure to etoposide...
May 24, 2016: Oncotarget
Pamela Viani de Andrade, Augusto Faria Andrade, Rosane Gomes de Paula Queiroz, Carlos Alberto Scrideli, Luiz Gonzaga Tone, Elvis Terci Valera
BACKGROUND: Glioblastoma (GBM) is considered to be one of the most aggressive tumors of the central nervous system (CNS). Even with the use of modern treatment protocols, the prognosis remains reserved, with children with GBM having a mean survival of 12-15 months. METHODS: In the present study we investigated the potential radiosensitizing effect of PCI-24781, a potent pan-histone deacetylase inhibitor (HDACi), on the SF188 and KNS42 cell lines of pediatric GBM...
2016: Cancer Cell International
Yu Takada, Masanori Someya, Yoshihisa Matsumoto, Masaaki Satoh, Kensei Nakata, Masakazu Hori, Masato Saito, Naoki Hirokawa, Kunihiko Tateoka, Mizue Teramoto, Tsuyoshi Saito, Tadashi Hasegawa, Koh-Ichi Sakata
DNA double-strand breaks (DSB) are severe damages induced by ionizing radiation. Non-homologous end joining (NHEJ) is a major mechanism for repairing DSB. Immunohistochemical analysis of proteins involved in NHEJ, such as Ku86 and XRCC4 (X-ray repair cross-complementing protein 4) may be useful for predicting tumor radiosensitivity. We examined the relationship between expression of DSB-related proteins in biopsy specimens of uterine cervical cancer and the pathological effect of 40 Gy of preoperative radiotherapy...
February 11, 2016: Medical Molecular Morphology
Ga-Young Kang, Eun-Ho Kim, Hae-June Lee, Na-Yeon Gil, Hyuk-Jin Cha, Yun-Sil Lee
A novel role for HSF1 as an inhibitor of non-homologous end joining (NHEJ) repair activity was identified. HSF1 interacted directly with both of the N-terminal sequences of the Ku70 and Ku86 proteins, which inhibited the endogenous heterodimeric interaction between Ku70 and Ku86. The blocking of the Ku70 and Ku86 interaction by HSF1 induced defective NHEJ repair activity and ultimately activated genomic instability after ionizing radiation (IR), which was similar to effects seen in Ku70 or Ku80 knockout cells...
October 6, 2015: Oncotarget
Lucia Hiľovská, Rastislav Jendželovský, Zuzana Jendželovská, Ján Kovaľ, Peter Fedoročko
Multidrug resistance caused by the overexpression of ABC transporter proteins in cancer cells remains a major obstacle limiting chemotherapy efficacy. Drugs inhibiting these transporters have been shown to increase the anti-proliferative properties of chemotherapeutics. As we previously described, proadifen, a P450 monooxygenase inhibitor, might also be able to inhibit some ABC transporters, including breast cancer resistance protein (BCRP). Because mitoxantrone (MTX) is a strong BCRP substrate and is often used in the treatment of leukemia, we investigated the effect of 24 h proadifen pre-treatment on the cytotoxicity of MTX in leukemic cell lines that are sensitive to MTX (HL-60) and MTX-resistant ABCG2-overexpressing subclone (cBCRP)...
October 2015: International Journal of Oncology
M Kano, K Matsushita, B Rahmutulla, S Yamada, H Shimada, S Kubo, T Hiwasa, H Matsubara, F Nomura
Combination therapy of carbon-ion beam with the far upstream element-binding protein (FBP)-interacting repressor, FIR, which interferes with DNA damage repair proteins, was proposed as an approach for esophageal cancer treatment with low side effects regardless of TP53 status. In vivo therapeutic antitumor efficacy of replication-defective adenovirus (E1 and E3 deleted adenovirus serotype 5) encoding human FIR cDNA (Ad-FIR) was demonstrated in the tumor xenograft model of human esophageal squamous cancer cells, TE-2...
January 2016: Gene Therapy
A Craxton, J Somers, D Munnur, R Jukes-Jones, K Cain, M Malewicz
Repair of double-stranded DNA breaks (DSBs) in mammalian cells primarily occurs by the non-homologous end-joining (NHEJ) pathway, which requires seven core proteins (Ku70/Ku86, DNA-PKcs (DNA-dependent protein kinase catalytic subunit), Artemis, XRCC4-like factor (XLF), XRCC4 and DNA ligase IV). Here we show using combined affinity purification and mass spectrometry that DNA-PKcs co-purifies with all known core NHEJ factors. Furthermore, we have identified a novel evolutionary conserved protein associated with DNA-PKcs-c9orf142...
June 2015: Cell Death and Differentiation
Na Li, Marcus Parrish, Tze Khee Chan, Lu Yin, Prashant Rai, Yamada Yoshiyuki, Nona Abolhassani, Kong Bing Tan, Orsolya Kiraly, Vincent T K Chow, Bevin P Engelward
Influenza viruses account for significant morbidity worldwide. Inflammatory responses, including excessive generation of reactive oxygen and nitrogen species (RONS), mediate lung injury in severe influenza infections. However, the molecular basis of inflammation-induced lung damage is not fully understood. Here, we studied influenza H1N1 infected cells in vitro, as well as H1N1 infected mice, and we monitored molecular and cellular responses over the course of 2 weeks in vivo. We show that influenza induces DNA damage to both, when cells are directly exposed to virus in vitro (measured using the comet assay) and also when cells are exposed to virus in vivo (estimated via γH2AX foci)...
August 2015: Cellular and Molecular Life Sciences: CMLS
Bahityar Rahmutulla, Kazuyuki Matsushita, Mamoru Satoh, Masanori Seimiya, Sachio Tsuchida, Shuji Kubo, Hideaki Shimada, Masayuki Ohtsuka, Masaru Miyazaki, Fumio Nomura
The far-upstream element-binding protein-interacting repressor (FIR) is a c-myc transcriptional suppressor. FIR is alternatively spliced to lack the transcriptional repression domain within exon 2 (FIRΔexon2) in colorectal cancers. FIR and FIRΔexon2 form homo- or heterodimers that complex with SAP155. SAP155, a subunit of the essential splicing factor 3b subcomplex in the spliceosome, is required for proper P27Kip1 pre-mRNA splicing, and P27Kip1 arrests cells at G1. In contrast, FIR was co-immunoprecipitated with Ku86 and DNA-PKcs...
May 15, 2014: Oncotarget
Lei Chu, Xiajun Zhang, Guozhong Wang, Wenjun Zhou, Zhongxiang Du, Anding Liu, Hong Zhao
OBJECTIVE: To investigate the clinical value of serum anti-Ku86 in early detection of hepatocellular carcinoma (HCC). METHODS: Expression levels of Ku86 protein in HCC and adjacent normal liver tissues were detected by Western blotting. Serum anti-Ku86 level in 83 patients with early HCC and 124 patients with liver cirrhosis were detected by enzyme-linked immunosorbent assay (ELISA). Chemiluminescence was used to measure the serum level of α-fetoprotein (AFP). RESULTS: Expression of Ku86 protein in HCC was increased when compared with the adjacent normal liver tissues (0...
February 2014: Zhonghua Zhong Liu za Zhi [Chinese Journal of Oncology]
Julio C Morales, Patricia Richard, Amy Rommel, Farjana J Fattah, Edward A Motea, Praveen L Patidar, Ling Xiao, Konstantin Leskov, Shwu-Yuan Wu, Walter N Hittelman, Cheng-Ming Chiang, James L Manley, David A Boothman
Functions of Kub5-Hera (In Greek Mythology Hera controlled Artemis) (K-H), the human homolog of the yeast transcription termination factor Rtt103, remain undefined. Here, we show that K-H has functions in both transcription termination and DNA double-strand break (DSB) repair. K-H forms distinct protein complexes with factors that repair DSBs (e.g. Ku70, Ku86, Artemis) and terminate transcription (e.g. RNA polymerase II). K-H loss resulted in increased basal R-loop levels, DSBs, activated DNA-damage responses and enhanced genomic instability...
April 2014: Nucleic Acids Research
Yong Xu, Ai-Jun Liu, Yuan-Xing Gao, Ming-Gen Hu, Guo-Dong Zhao, Zhi-Ming Zhao, Rong Liu
BACKGROUND: Hepatocellular carcinoma (HCC) is a common disease and the third leading cause of cancer-related deaths worldwide. Level of the 82-kDa ATP-dependent DNA helicase II (Ku86) increases in some tumors, but its clinical use as a marker for HCC is rare. AIMS: To examine the relationship between increases in Ku86 and the development of hepatitis B virus (HBV)-related HCC to define the relationship between Ku86 and HCC. METHODS: Expression of Ku86 in tumor tissue, para-tumor tissue, and normal tissue was examined by immunohistochemistry, and Ku86 antibody titers in patient serum collected pre- and post-operatively were measured by ELISA...
March 2014: Digestive Diseases and Sciences
Manjula Gorre, Prajitha Edathara Mohandas, Sailaja Kagita, Sandhya Annamaneni, Raghunadharao Digumarti, Vishnupriya Satti
Double-strand breaks (DSBs) inducing agents influence the fidelity of DNA repair in both normal cells and leukemic cells, causing major genomic instability. In eukaryotic cells, non-homologous end joining pathway (NHEJ) is the major mechanism for DSB repair. Human X-ray repair cross-complementing 5 (XRCC5) gene encodes for the protein KU86, an important component of NHEJ pathway. Variable number of tandem repeats (VNTR) polymorphism (rs 6147172) in the promoter region of XRCC5 gene was shown to have effect on gene expression and was found to be associated with the development of several cancers...
February 2014: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Khalil Abdelbaqi, Domenic Di Paola, Emmanouil Rampakakis, Maria Zannis-Hadjopoulos
Human origins of DNA replication are specific sequences within the genome whereby DNA replication is initiated. A select group of proteins, known as the pre-replication (pre-RC) complex, in whose formation the Ku protein (Ku70/Ku86) was shown to play a role, bind to replication origins to initiate DNA replication. In this study, we have examined the involvement of Ku in breast tumorigenesis and tumor progression and found that the Ku protein expression levels in human breast metastatic (MCF10AC1a) cells were higher in the chromatin fraction compared to hyperplastic (MCF10AT) and normal (MCF10A) human breast cells, but remained constant in both the nuclear and cytoplasmic fractions...
2013: Journal of Cancer
Yi Xiao, Jungang Chen, Qingjiao Liao, Yang Wu, Can Peng, Xulin Chen
Kaposi's sarcoma-associated herpesvirus (KSHV) has been associated with the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. Cytogenetic studies have revealed chromosome abnormalities in KS tissues, including recurring copy number changes in chromosomes and the loss of chromosomes. Unfaithful DNA repair may contribute to the genomic instability that is one of the most common hallmarks of tumours. We found that lytic infection of KSHV can cause severe DNA double-strand breaks (DSBs) and impair non-homologous end joining (NHEJ) in host cells...
August 2013: Journal of General Virology
Yikun Li, Xuerong Wang, Ping Yue, Hui Tao, Suresh S Ramalingam, Taofeek K Owonikoko, Xingming Deng, Ya Wang, Haian Fu, Fadlo R Khuri, Shi-Yong Sun
BACKGROUND: The mechanisms underlying rapamycin-induced Akt phosphorylation have not been fully elucidated. RESULTS: Inhibition of PP2A or DNA-PK attenuates or abrogates rapamycin-induced Akt phosphorylation and co-inhibition of mTOR and DNA-PK enhances anticancer activity. CONCLUSION: PP2A-dependent and DNA-PK-mediated mechanism is involved in rapamycin-induced Akt phosphorylation. SIGNIFICANCE: A previously unknown mechanism underlying rapamycin-induced Akt phosphorylation and a novel strategy to enhance mTOR-targeted cancer therapy may be suggested...
May 10, 2013: Journal of Biological Chemistry
Sehyun Oh, Yongbao Wang, Jacob Zimbric, Eric A Hendrickson
Classic non-homologous end joining (C-NHEJ) is the predominant DNA double-strand break repair pathway in humans. Although seven genes Ku70, Ku86, DNA-PK(cs), Artemis, DNA Ligase IV (LIGIV), X-ray cross-complementing group 4 and XRCC4-like factor are required for C-NHEJ, several of them also have ancillary functions. For example, Ku70:Ku86 possesses an essential telomere maintenance activity. In contrast, LIGIV is believed to function exclusively in C-NHEJ. Moreover, a viable LIGIV-null human B-cell line and LIGIV-reduced patient cell lines have been described...
February 1, 2013: Nucleic Acids Research
Hiroyuki Mizuguchi, Kohei Miyagi, Takuma Terao, Noriko Sakamoto, Yosuke Yamawaki, Tsubasa Adachi, Shohei Ono, Yohei Sasaki, Yoshiyuki Yoshimura, Yoshiaki Kitamura, Noriaki Takeda, Hiroyuki Fukui
Histamine H(1) receptor (H1R) gene is up-regulated in patients with allergic rhinitis, and its expression level strongly correlates with the severity of symptoms. However, the mechanism underlying this remains unknown. Here we report the mechanism of H1R gene up-regulation. The luciferase assay revealed the existence of two promoter regions, A and B1. Two AP-1 and one Ets-1 bound to region A, while Ku86, Ku70, and PARP-1 bound to region B1. Ku86 was responsible for DNA binding and poly(ADP-ribosyl)ated in response to phorbol-12-myristate-13-acetate stimulation, inducing its dissociation from region B1 that is crucial for promoter activity...
2012: Scientific Reports
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