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https://www.readbyqxmd.com/read/29244158/znf830-mediates-cancer-chemoresistance-through-promoting-homologous-recombination-repair
#1
Guo Chen, Jianxiang Chen, Yiting Qiao, Yaru Shi, Wei Liu, Qi Zeng, Hui Xie, Xiaorui Shi, Youwei Sun, Xu Liu, Tongyu Li, Liqian Zhou, Jianqin Wan, Tian Xie, Hangxiang Wang, Fu Wang
Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to chemotherapy and radiotherapy in human cancers. However, the mechanisms of HR repair in treatment resistance for the improvement of cancer therapy remains unclear. Here, we report that the zinc finger protein 830 (ZNF830) promotes HR repair and the survival of cancer cells in response to DNA damage. Mechanistically, ZNF830 directly participates in DNA end resection via interacting with CtIP and regulating CtIP recruitment to DNA damage sites...
December 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29244155/differential-rpa-1-and-rad-51-recruitment-in-vivo-throughout-the-c-elegans-germline-as-revealed-by-laser-microirradiation
#2
Emily Koury, Kailey Harrell, Sarit Smolikove
Studies of the repair pathways associated with DNA double strand breaks (DSBs) are numerous, and provide evidence for cell-cycle specific regulation of homologous recombination (HR) by the regulation of its associated proteins. Laser microirradiation is a well-established method to examine in vitro kinetics of repair and allows for live-imaging of DSB repair from the moment of induction. Here we apply this method to whole, live organisms, introducing an effective system to analyze exogenous, microirradiation-induced breaks in the Caenorhabditis elegans germline...
December 13, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29243925/in-vitro-bypass-of-thymidine-glycol-by-dna-polymerase-%C3%AE-forms-sequence-dependent-frameshift-mutations
#3
Daniel J Laverty, Marc M Greenberg
Unrepaired DNA lesions block replication and threaten genomic stability. Several specialized translesion polymerases, including polymerase θ (Pol θ), contribute to replicative bypass of these lesions. The role of Pol θ in double-strand break repair is well-understood, but its contribution to translesion synthesis is much less so. We describe the action of Pol θ on templates containing thymidine glycol (Tg), a major cytotoxic, oxidative DNA lesion that blocks DNA replication. Unrepaired Tg lesions are bypassed in human cells by specialized translesion polymerases by one of two distinct pathways: high-fidelity bypass by the combined action of Pol κ and Pol ζ or weakly mutagenic bypass by Pol θ...
December 15, 2017: Biochemistry
https://www.readbyqxmd.com/read/29240558/a-modified-microdosimetric-kinetic-model-for-relative-biological-effectiveness-calculation
#4
Yizheng Chen, Junli Li, Chunyan Li, Rui Qiu, Zhen Wu
In the heavy ion therapy, not only the distribution of physical absorbed dose, but also the relative biological effectiveness (RBE) weighted dose needs to be taken into account. The microdosimetric kinetic model (MKM) can predict the RBE value of heavy ions with saturation-corrected dose-mean specific energy, which has been used in clinical treatment planning at the National Institute of Radiological Sciences. In the theoretical assumption of the MKM, the yield of the primary lesion is independent of the radiation quality, while the experimental data shows that DNA double strand break (DSB) yield, considered as the main primary lesion, depends on the LET of the particle...
December 14, 2017: Physics in Medicine and Biology
https://www.readbyqxmd.com/read/29237014/the-effect-of-stochasticity-on-repair-of-dna-double-strand-breaks-throughout-non-homologous-end-joining-pathway
#5
Fazeleh S Mohseni-Salehi, Fatemeh Zare-Mirakabad, Soudeh Ghafouri-Fard, Mehdi Sadeghi
DNA double strand breaks (DSBs) are the most lethal lesions of DNA induced by ionizing radiation, industrial chemicals and a wide variety of drugs used in chemotherapy. In the context of DNA damage response system modelling, uncertainty may arise in several ways such as number of induced DSBs, kinetic rates and measurement error in observable quantities. Therefore, using the stochastic approaches is imperative to gain further insight into the dynamic behaviour of DSBs repair process. In this article, a continuous-time Markov chain (CTMC) model of the non-homologous end joining (NHEJ) mechanism is formulated according to the DSB complexity...
December 8, 2017: Mathematical Medicine and Biology: a Journal of the IMA
https://www.readbyqxmd.com/read/29236199/caspase-cleavage-of-transcription-factor-sp1-enhances-apoptosis
#6
Behzad Torabi, Samuel Flashner, Kate Beishline, Aislinn Sowash, Kelly Donovan, Garrett Bassett, Jane Azizkhan-Clifford
Sp1 is a ubiquitous transcription factor that regulates many genes involved in apoptosis and senescence. Sp1 also has a role in the DNA damage response; at low levels of DNA damage, Sp1 is phosphorylated by ATM and localizes to double-strand break sites where it facilitates DNA double-strand-break repair. Depletion of Sp1 increases the sensitivity of cells to DNA damage, whereas overexpression of Sp1 can drive cells into apoptosis. In response to a variety of stimuli, Sp1 can be regulated through proteolytic cleavage by caspases and/or degradation...
December 13, 2017: Apoptosis: An International Journal on Programmed Cell Death
https://www.readbyqxmd.com/read/29234069/the-human-dna-glycosylases-neil1-and-neil3-excise-psoralen-induced-dna-dna-cross-links-in-a-four-stranded-dna-structure
#7
Peter R Martin, Sophie Couvé, Caroline Zutterling, Mustafa S Albelazi, Regina Groisman, Bakhyt T Matkarimov, Jason L Parsons, Rhoderick H Elder, Murat K Saparbaev
Interstrand cross-links (ICLs) are highly cytotoxic DNA lesions that block DNA replication and transcription by preventing strand separation. Previously, we demonstrated that the bacterial and human DNA glycosylases Nei and NEIL1 excise unhooked psoralen-derived ICLs in three-stranded DNA via hydrolysis of the glycosidic bond between the crosslinked base and deoxyribose sugar. Furthermore, NEIL3 from Xenopus laevis has been shown to cleave psoralen- and abasic site-induced ICLs in Xenopus egg extracts. Here we report that human NEIL3 cleaves psoralen-induced DNA-DNA cross-links in three-stranded and four-stranded DNA substrates to generate unhooked DNA fragments containing either an abasic site or a psoralen-thymine monoadduct...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29234047/inhibition-of-nhej-repair-by-type-ii-a-crispr-cas-systems-in-bacteria
#8
Aude Bernheim, Alicia Calvo-Villamañán, Clovis Basier, Lun Cui, Eduardo P C Rocha, Marie Touchon, David Bikard
Type II CRISPR-Cas systems introduce double-strand breaks into DNA of invading genetic material and use DNA fragments to acquire novel spacers during adaptation. These breaks can be the substrate of several DNA repair pathways, paving the way for interactions. We report that non-homologous end-joining (NHEJ) and type II-A CRISPR-Cas systems only co-occur once among 5563 fully sequenced prokaryotic genomes. We investigated experimentally the possible molecular interactions using the NHEJ pathway from Bacillus subtilis and the type II-A CRISPR-Cas systems from Streptococcus thermophilus and Streptococcus pyogenes...
December 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29234018/dynamics-of-rif1-sumoylation-is-regulated-by-pias4-in-the-maintenance-of-genomic-stability
#9
Ramesh Kumar, Cheok Chit Fang
RIF1 plays a key role in inhibiting DNA end resection and promoting NHEJ mediated DNA double stand break repair in G1. However, whether SUMOlyation may regulate RIF1 functions is still largely unknown. Here, we report that RIF1 is SUMOlyated in response to DNA damage. We identified PIAS4 as the primary SUMO E3 ligase required for the SUMOylation of RIF1 protein. Mammalian cells compromised of PIAS4 expression, show impaired RIF1 SUMOylation and defective for the disassembly of DNA damage responsive RIF1 foci...
December 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29233683/caspase-mediated-cleavage-of-x-ray-repair-cross-complementing-group-4-promotes-apoptosis-by-enhancing-nuclear-translocation-of-caspase-activated-dnase
#10
Yumi Sunatani, Radhika Pankaj Kamdar, Mukesh Kumar Sharma, Tadashi Matsui, Ryo Sakasai, Mitsumasa Hashimoto, Yasuhito Ishigaki, Yoshihisa Matsumoto, Kuniyoshi Iwabuchi
X-ray repair cross-complementing group 4 (XRCC4), a repair protein for DNA double-strand breaks, is cleaved by caspases during apoptosis. In this study, we examined the role of XRCC4 in apoptosis. Cell lines, derived from XRCC4-deficient M10 mouse lymphoma cells and stably expressing wild-type XRCC4 or caspase-resistant XRCC4, were established and treated with staurosporine (STS) to induce apoptosis. In STS-induced apoptosis, expression of wild-type, but not caspase-resistant, XRCC4 in XRCC4-deficient cells enhanced oligonucleosomal DNA fragmentation and the appearance of TUNEL-positive cells by promoting nuclear translocation of caspase-activated DNase (CAD), a major nuclease for oligonucleosomal DNA fragmentation...
December 9, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/29232400/biological-characterization-of-a-novel-in-vitro-cell-irradiator
#11
Tyler L Fowler, Michael M Fisher, Alison M Bailey, Bryan P Bednarz, Randall J Kimple
To evaluate the overall robustness of a novel cellular irradiator we performed a series of well-characterized, dose-responsive assays to assess the consequences of DNA damage. We used a previously described novel irradiation system and a traditional 137Cs source to irradiate a cell line. The generation of reactive oxygen species was assessed using chloromethyl-H2DCFDA dye, the induction of DNA DSBs was observed using the comet assay, and the initiation of DNA break repair was assessed through γH2AX image cytometry...
2017: PloS One
https://www.readbyqxmd.com/read/29232380/inhibition-of-grp78-abrogates-radioresistance-in-oropharyngeal-carcinoma-cells-after-egfr-inhibition-by-cetuximab
#12
Chaonan Sun, Chuyang Han, Yuanjun Jiang, Ning Han, Miao Zhang, Guang Li, Qiao Qiao
The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER) homeostatic state and result in ER stress (ERS), subsequently causing resistance to radiation and drugs...
2017: PloS One
https://www.readbyqxmd.com/read/29232168/high-throughput-screening-approach-for-identifying-compounds-that-inhibit-nonhomologous-end-joining
#13
Andrea L Bredemeyer, Bruce S Edwards, Mark K Haynes, Abigail J Morales, Yinan Wang, Oleg Ursu, Anna Waller, Larry A Sklar, Barry P Sleckman
DNA double-strand breaks (DSBs) are repaired primarily by homologous recombination (HR) or nonhomologous end joining (NHEJ). Compounds that modulate HR have shown promise as cancer therapeutics. The V(D)J recombination reaction, which assembles antigen receptor genes in lymphocytes, is initiated by the introduction of DNA DSBs at two recombining gene segments by the RAG endonuclease, followed by the NHEJ-mediated repair of these DSBs. Here, using HyperCyt automated flow cytometry, we develop a robust high-throughput screening (HTS) assay for NHEJ that utilizes engineered pre-B-cell lines where the V(D)J recombination reaction can be induced and monitored at a single-cell level...
December 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/29231883/silver-nanoparticles-in-the-lung-toxic-effects-and-focal-accumulation-of-silver-in-remote-organs
#14
Martin Wiemann, Antje Vennemann, Franziska Blaske, Michael Sperling, Uwe Karst
The distribution of silver (Ag) into remote organs secondary to the application of Ag nanoparticles (Ag-NP) to the lung is still incompletely understood and was investigated in the rat with imaging methods. Dose-finding experiments were carried out with 50 nm- or 200 nm-sized polyvinyl pyrrolidine (PVP)-coated Ag-NP using alveolar macrophages in vitro and female rats, which received Ag-NP via intratracheal instillation. In the main study, we administered 37.5-300 µg per rat lung of the more toxic Ag50-PVP and assessed the broncho-alveolar lavage fluid (BALF) for inflammatory cells, total protein and fibronectin after three and 21 days...
December 12, 2017: Nanomaterials
https://www.readbyqxmd.com/read/29231811/genome-wide-mapping-of-sister-chromatid-exchange-events-in-single-yeast-cells-using-strand-seq
#15
Clémence Claussin, David Porubský, Diana Cj Spierings, Nancy Halsema, Stefan Rentas, Victor Guryev, Peter M Lansdorp, Michael Chang
Homologous recombination involving sister chromatids is the most accurate, and thus most frequently used, form of recombination-mediated DNA repair. Despite its importance, sister chromatid recombination is not easily studied because it does not result in a change in DNA sequence, making recombination between sister chromatids difficult to detect. We have previously developed a novel DNA template strand sequencing technique, called Strand-seq, that can be used to map sister chromatid exchange (SCE) events genome-wide in single cells...
December 12, 2017: ELife
https://www.readbyqxmd.com/read/29230817/ebv-encoded-mirnas-target-atm-mediated-response-in-nasopharyngeal-carcinoma
#16
Raymond W-M Lung, Pok-Man Hau, Ken H-O Yu, Kevin Y Yip, Joanna H-M Tong, W-P Chak, Anthony W-H Chan, Ka-Hei Lam, Angela K-F Lo, Edith K-Y Tin, Shuk-Ling Chau, Jesse C-S Pang, Johnny S-H Kwan, Pierre Busson, Lawrence S Young, Lee-Fah Yap, Sai-Wah Tsao, Ka-Fai To, Kwok-Wai Lo
Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV-encoded miRNAs derived from BamH1-A rightward transcripts are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV-positive NPC cell line by small RNA sequencing...
December 12, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/29229995/lysyl-oxidase-like-3-is-required-for-melanoma-cell-survival-by-maintaining-genomic-stability
#17
Patricia G Santamaría, Alfredo Floristán, Bárbara Fontanals-Cirera, Alberto Vázquez-Naharro, Vanesa Santos, Saleta Morales, Lourdes Yuste, Héctor Peinado, Antonio García-Gómez, Francisco Portillo, Eva Hernando, Amparo Cano
Lysyl oxidase-like 3 (LOXL3) is a member of the lysyl oxidase family comprising multifunctional enzymes with depicted roles in extracellular matrix maturation, tumorigenesis, and metastasis. In silico expression analyses followed by experimental validation in a comprehensive cohort of human cell lines revealed a significant upregulation of LOXL3 in human melanoma. We show that LOXL3 silencing impairs cell proliferation and triggers apoptosis in various melanoma cell lines. Further supporting a pro-oncogenic role in melanoma, LOXL3 favors tumor growth in vivo and cooperates with oncogenic BRAF in melanocyte transformation...
December 11, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29229926/cell-cycle-dependent-phosphorylation-regulates-recql4-pathway-choice-and-ubiquitination-in-dna-double-strand-break-repair
#18
Huiming Lu, Raghavendra A Shamanna, Jessica K de Freitas, Mustafa Okur, Prabhat Khadka, Tomasz Kulikowicz, Priscella P Holland, Jane Tian, Deborah L Croteau, Anthony J Davis, Vilhelm A Bohr
Pathway choice within DNA double-strand break (DSB) repair is a tightly regulated process to maintain genome integrity. RECQL4, deficient in Rothmund-Thomson Syndrome, promotes the two major DSB repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). Here we report that RECQL4 promotes and coordinates NHEJ and HR in different cell cycle phases. RECQL4 interacts with Ku70 to promote NHEJ in G1 when overall cyclin-dependent kinase (CDK) activity is low. During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs...
December 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/29228718/increased-single-strand-annealing-rather-than-non-homologous-end-joining-predicts-hereditary-ovarian-carcinoma
#19
Miriam Deniz, Tatiana Romashova, Sarah Kostezka, Anke Faul, Theresa Gundelach, Maria Moreno-Villanueva, Wolfgang Janni, Thomas W P Friedl, Lisa Wiesmüller
Mutations in genes encoding DNA double-strand break (DSB) repair components, especially homologous recombination (HR) proteins, were found to predispose to breast and ovarian cancer. Beyond high penetrance risk gene mutations underlying monogenic defects, low risk gene mutations generate polygenic defects, enlarging the fraction of individuals with a predisposing phenotype. DSB repair dysfunction opens new options for targeted therapies; poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for BRCA-mutated and platinum-responsive ovarian cancers...
November 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228626/boosting-the-effects-of-hyperthermia-based-anticancer-treatments-by-hsp90-inhibition
#20
Lianne E M Vriend, Nathalie van den Tempel, Arlene L Oei, Mike L'Acosta, Frederique J Pieterson, Nicolaas A P Franken, Roland Kanaar, Przemek M Krawczyk
Hyperthermia - application of supra-physiological temperatures to cells, tissues or organs - is a pleiotropic treatment that affects most aspects of cellular metabolism, but its effects on DNA are of special interest in the context of cancer research and treatment. Hyperthermia inhibits repair of various DNA lesions, including double-strand breaks (DSBs), making it a powerful radio- and chemosensitizer, with proven clinical efficacy in therapy of various types of cancer, including tumors of head and neck, bladder, breast and cervix...
November 14, 2017: Oncotarget
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