Academic literature on the topic 'Double-Stranded DNA Breaks'
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Journal articles on the topic "Double-Stranded DNA Breaks"
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Goodsell, David S. "The Molecular Perspective: Double-Stranded DNA Breaks." Stem Cells 23, no. 7 (August 2005): 1021–22. http://dx.doi.org/10.1634/stemcells.fcm4.
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Goodsell, David S. "The Molecular Perspective: Double‐Stranded DNA Breaks." Oncologist 10, no. 5 (May 2005): 361–62. http://dx.doi.org/10.1634/theoncologist.10-5-361.
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Zee, Yeng Peng, Carmen López-Fernández, F. Arroyo, Stephen D. Johnston, William V. Holt, and Jaime Gosalvez. "Evidence that single-stranded DNA breaks are a normal feature of koala sperm chromatin, while double-stranded DNA breaks are indicative of DNA damage." REPRODUCTION 138, no. 2 (August 2009): 267–78. http://dx.doi.org/10.1530/rep-09-0021.
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In this study, we have used single and double comet assays to differentiate between single- and double-stranded DNA damage in an effort to refine the interpretation of DNA damage in mature koala spermatozoa. We have also investigated the likelihood that single-stranded DNA breakage is part of the natural spermiogenic process in koalas, where its function would be the generation of structural bends in the DNA molecule so that appropriate packaging and compaction can occur. Koala spermatozoa were examined using the sperm chromatin dispersion test (SCDt) and comet assays to investigate non-orthodox double-stranded DNA. Comet assays were conducted under 1) neutral conditions; and 2) neutral followed by alkaline conditions (double comet assay); the latter technique enabled simultaneous visualisation of both single-stranded and double-stranded DNA breaks. Following the SCDt, there was a continuum of nuclear morphotypes, ranging from no apparent DNA fragmentation to those with highly dispersed and degraded chromatin. Dispersion morphotypes were mirrored by a similar diversity of comet morphologies that could be further differentiated using the double comet assay. The majority of koala spermatozoa had nuclei with DNA abasic-like residues that produced single-tailed comets following the double comet assay. The ubiquity of these residues suggests that constitutive alkali-labile sites are part of the structural configuration of the koala sperm nucleus. Spermatozoa with ‘true’ DNA fragmentation exhibited a continuum of comet morphologies, ranging from a more severe form of alkaline-susceptible DNA with a diffuse single tail to nuclei that exhibited both single- and double-stranded breaks with two comet tails.
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Komor, Alexis C., Ahmed H. Badran, and David R. Liu. "Editing the Genome Without Double-Stranded DNA Breaks." ACS Chemical Biology 13, no. 2 (October 9, 2017): 383–88. http://dx.doi.org/10.1021/acschembio.7b00710.
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Hanada, Katsuhiro, Teruhito Yamashita, Yuko Shobuike, and Hideo Ikeda. "Role of DnaB Helicase in UV-Induced Illegitimate Recombination in Escherichia coli." Journal of Bacteriology 183, no. 17 (September 1, 2001): 4964–69. http://dx.doi.org/10.1128/jb.183.17.4964-4969.2001.
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ABSTRACT To study the involvement of DNA replication in UV-induced illegitimate recombination, we examined the effect of temperature-sensitive dnaB mutations on illegitimate recombination and found that the frequency of illegitimate recombination was reduced by an elongation-deficient mutation,dnaB14, but not by an initiation-deficient mutation,dnaB252. This result indicates that DNA replication is required for UV-induced illegitimate recombination. In addition, thednaB14 mutation also affected spontaneous or UV-induced illegitimate recombination enhanced by the recQmutation. Nucleotide sequence analyses of the recombination junctions showed that DnaB-mediated illegitimate recombination is short homology dependent. Previously, Michel et al. (B. Michel, S. Ehrlich, and M. Uzest, EMBO J. 16:430–438, 1997) showed that thermal treatment of the temperature-sensitive dnaB8 mutant induces double-stranded breaks, implying that induction of illegitimate recombination occurs. To explain the discrepancy between the observations, we propose a model for DnaB function, in which thednaB mutations may exhibit two types of responses, early and late responses, for double-stranded break formation. In the early response, replication forks stall at damaged DNA, resulting in the formation of double-stranded breaks, and the dnaB14mutation reduces the double-stranded breaks shortly after temperature shift-up. On the other hand, in the late response, the arrested replication forks mediated by the dnaB8 mutation may induce double-stranded breaks after prolonged incubation.
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Cowan, Richard, David Culpin, and David Gates. "Asymptotic results for a problem of DNA breakage." Journal of Applied Probability 27, no. 2 (June 1990): 433–39. http://dx.doi.org/10.2307/3214663.
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Double-stranded DNA molecules can be damaged by enzymic action or radiation, in a manner which creates randomly-located single-stranded breaks (nicks). The accumulation of these leads eventually to the double-stranded breakage of the molecule, because two opposite-strand nicks within a critical distance of each other establish conditions for breakage. We study the random variable N, defined as the number of nicks needed for double-stranded breakage to occur. We develop an asymptotic theory which is needed for practical computations.
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Cowan, Richard, David Culpin, and David Gates. "Asymptotic results for a problem of DNA breakage." Journal of Applied Probability 27, no. 02 (June 1990): 433–39. http://dx.doi.org/10.1017/s0021900200038894.
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Double-stranded DNA molecules can be damaged by enzymic action or radiation, in a manner which creates randomly-located single-stranded breaks (nicks). The accumulation of these leads eventually to the double-stranded breakage of the molecule, because two opposite-strand nicks within a critical distance of each other establish conditions for breakage. We study the random variable N, defined as the number of nicks needed for double-stranded breakage to occur. We develop an asymptotic theory which is needed for practical computations.
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Dillingham, Mark S., and Stephen C. Kowalczykowski. "RecBCD Enzyme and the Repair of Double-Stranded DNA Breaks." Microbiology and Molecular Biology Reviews 72, no. 4 (December 2008): 642–71. http://dx.doi.org/10.1128/mmbr.00020-08.
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SUMMARY The RecBCD enzyme of Escherichia coli is a helicase-nuclease that initiates the repair of double-stranded DNA breaks by homologous recombination. It also degrades linear double-stranded DNA, protecting the bacteria from phages and extraneous chromosomal DNA. The RecBCD enzyme is, however, regulated by a cis-acting DNA sequence known as Chi (crossover hotspot instigator) that activates its recombination-promoting functions. Interaction with Chi causes an attenuation of the RecBCD enzyme's vigorous nuclease activity, switches the polarity of the attenuated nuclease activity to the 5′ strand, changes the operation of its motor subunits, and instructs the enzyme to begin loading the RecA protein onto the resultant Chi-containing single-stranded DNA. This enzyme is a prototypical example of a molecular machine: the protein architecture incorporates several autonomous functional domains that interact with each other to produce a complex, sequence-regulated, DNA-processing machine. In this review, we discuss the biochemical mechanism of the RecBCD enzyme with particular emphasis on new developments relating to the enzyme's structure and DNA translocation mechanism.
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Eid, Ayman, Sahar Alshareef, and Magdy M. Mahfouz. "CRISPR base editors: genome editing without double-stranded breaks." Biochemical Journal 475, no. 11 (June 11, 2018): 1955–64. http://dx.doi.org/10.1042/bcj20170793.
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The CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 adaptive immunity system has been harnessed for genome editing applications across eukaryotic species, but major drawbacks, such as the inefficiency of precise base editing and off-target activities, remain. A catalytically inactive Cas9 variant (dead Cas9, dCas9) has been fused to diverse functional domains for targeting genetic and epigenetic modifications, including base editing, to specific DNA sequences. As base editing does not require the generation of double-strand breaks, dCas9 and Cas9 nickase have been used to target deaminase domains to edit specific loci. Adenine and cytidine deaminases convert their respective nucleotides into other DNA bases, thereby offering many possibilities for DNA editing. Such base-editing enzymes hold great promise for applications in basic biology, trait development in crops, and treatment of genetic diseases. Here, we discuss recent advances in precise gene editing using different platforms as well as their potential applications in basic biology and biotechnology.
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Bhandoola, Avinash, Benjamin Dolnick, Nihal Fayad, Andre Nussenzweig, and Alfred Singer. "Immature Thymocytes Undergoing Receptor Rearrangements Are Resistant to an Atm-Dependent Death Pathway Activated in Mature T Cells by Double-Stranded DNA Breaks." Journal of Experimental Medicine 192, no. 6 (September 18, 2000): 891–98. http://dx.doi.org/10.1084/jem.192.6.891.
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Immature CD4+CD8+ thymocytes rearrange their T cell receptor (TCR)-α gene locus to generate clonotypic α/β TCR, after which a few cells expressing selectable TCR are signaled to further differentiate into mature T cells. Because of requirements for self-tolerance, immature CD4+CD8+ thymocytes are programmed to die in the thymus in response to a variety of stimuli that do not induce death of mature T cells. We now demonstrate that, in contrast to all previously described stimuli, immature CD4+CD8+ thymocytes are selectively more resistant than mature T cells to apoptotic death induced by DNA intercalating agents. Importantly, we demonstrate that DNA intercalating agents induce double-stranded DNA breaks in both immature thymocytes and mature T cells, but immature thymocytes tolerate these DNA breaks, whereas mature T cells are signaled to die by an Atm-dependent but p53-independent death mechanism. Thus, our results indicate that absence of an Atm-dependent but p53-independent pathway allows immature thymocytes to survive double-stranded DNA breaks. It is likely that the unique ability of immature thymocytes to survive DNA-damaging intercalating agents reflects their tolerance of double-stranded DNA breaks that occur normally during antigen receptor gene rearrangements.
Dissertations / Theses on the topic "Double-Stranded DNA Breaks"
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Traver, Brenna E. "Exogenously-introduced Homing Endonucleases Catalyze Double-stranded DNA Breaks in Aedes aegypti." Thesis, Virginia Tech, 2009. http://hdl.handle.net/10919/40967.
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Aedes aegypti transmits the viruses which cause yellow fever, dengue fever, and dengue hemorrhagic fever. Homing endonucleases are selfish genetic elements which introduce double-stranded DNA (dsDNA) breaks in a sequence-specific manner. In this study, we aimed to validate a somatic assay to detect recombinant homing endonuclease (rHE)-induced dsDNA breaks in both cultured cells and adult female Ae. aegypti. While the cell culture-based two plasmid assay used to test rHE ability to induce dsDNA breaks was inconclusive, assays used to test rHEs in Ae. aegypti were successful. Recognition sequences for various rHEs were introduced into Ae. aegypti through germline transformation, and imperfect repair at each of these exogenous sites was evaluated. In mosquitoes containing a single exogenous HE site, imperfect gap repair was detected in 40% and 21% of clones sequenced from mosquitoes exposed to I-PpoI and Iâ SceI, respectively. In mosquitoes containing two exogenous HE sites flanking a marker gene (EGFP), 100% of clones sequenced from mosquitoes exposed to I-PpoI, I-CreI, and I-AniI demonstrated excision of EGFP. No evidence of EGFP excision or imperfect repair at any HE recognition site was detected in mosquitoes not exposed to a rHE. In summary, a somatic genomic footprint assay was developed and validated to detect rHE or other meganuclease-induced site-specific dsDNA breaks in chromosomal DNA in Ae. aegypti.Master of Science in Life Sciences
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Stephanou, Nicolas Constantinos. "Mycobacterial non-homologous end-joining : molecular mechanisms and components of a novel DNA double strand break repair pathway /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1528973431&sid=21&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Aniukwu, Jideofor Flint. "The pathways and outcomes of mycobacterial NHEJ depend on the structure of the broken DNA ends /." Access full-text from WCMC :, 2008. http://proquest.umi.com/pqdweb?did=1555143361&sid=2&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Moore, Anne Margaret. "Identification and characterisation of novel plant specific regulators of cellular responses to double stranded DNA breaks." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/9504.
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The ability of organisms to sense and respond to challenges to their genome integrity is key to survival. In particular, the ability to detect and respond to double-stranded DNA breaks (DSBs) is of fundamental importance as not only are DSBs potentially lethal as they can trigger apoptosis, but there is also the potential for the loss of genetic information. The response to DSBs is well conserved across Eukaryotes and comprises two stages: detection of the break and subsequent remedial action. The remedial action involves cell cycle arrest, DNA repair, and, if repair cannot be effected, possible apoptosis. Whilst many of the key components, especially in the initial detection of the break, are conserved there are also differences between plants and animals in some of the main components and their roles. In this thesis I have proposed an overall framework for the cellular response to DSBs in plants and have proposed two candidate genes, TCP20 and SOG1, as novel plant specific activators in this response. Their suitability has been addressed by considering their activation and their downstream targets. I have shown that TCP20 is necessary for growth arrest observed in shoot apical meristems after exposure to genotoxic stress. I have also shown that activation of one of the key targets of TCP20, CYCB1;1 requires TCP20 and that a key TCP20 binding motif in the promoter of CYCB1;1 is necessary for the up-regulation of CYCB1;1 in response to genotoxic stress. This motif is over-represented in the promoters of many of the genes involved in DNA damage repair, suggesting that TCP20 plays a role in the co-ordination of the cellular response to DSBs.
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Yuan, Ying. "Modulation of DNA double strand breaks end-joining pathway choice by single stranded oligonucleotides in mammalian cells." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30091.
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En réponse aux dommages de son génome, le choix par la cellule de la voie de réparation de l'ADN est un crucial par ses conséquences en termes de mutagénèse et de survie. Pour faire face aux cassures double-brin de l'ADN (CDB), les cellules humaines possèdent deux voies principales qui consistent soit à rejoindre les extrémités de la cassure par jonction d'extrémités non-homologues (voie conventionnelle C-NHEJ), soit à reconstituer par recombinaison homologue la séquence clivée en copiant son double non endommagé présent après la réplication (voie RH). La RH nécessite de dégrader l'un des brins d'ADN de part et d'autre de la cassure. Cette dégradation produit de courts fragments d'ADN simple-brin, connus pour aider à signaler le dommage à la cellule. Dans ce travail, nous avons évalué directement l'effet de ces fragments d'ADN simple brin sur la réparation des CDB dans des expériences biochimiques et cellulaires. Nous montrons que de courts fragments d'ADN simple-brin inhibent la C-NHEJ en inactivant sa protéine clef Ku, tout en stimulant une forme minoritaire de jonction des cassures dite NHEJ alternative (A-EJ). Ces travaux permettent de mieux comprendre comment la réparation par la voie peu connue A-EJ peut s'exprimer dans les cellules mais aussi d'envisager des stratégies pour piloter la réponse des cellules cancéreuses aux thérapies induisant des CDBIn response to DNA damage, the choice made by the cells between DNA repair mechanisms is crucial for mutagenic and survival outcomes. In humans, DNA double-strand breaks are repaired by two mutually-exclusive mechanisms, homologous recombination or end-joining. Among end-joining mechanisms, the main process is classical non-homologous end-joining (C-NHEJ) which relies on Ku binding to DNA ends and DNA Ligase IV (Lig4)-mediated ligation. Mostly under Ku- or Lig4-defective conditions, an alternative end-joining process (A-EJ) can operate and exhibits a trend toward microhomology usage at the break junction. Homologous recombination relies on an initial MRN-dependent nucleolytic degradation of one strand at DNA ends. This process, named DNA resection generates 3' single-stranded tails necessary for homologous pairing with the sister chromatid. While it is believed from the current literature that the balance between joining and recombination processes at DSBs ends is mainly dependent on the initiation of resection, it has also been shown that MRN activity can generate short single-stranded DNA oligonucleotides (ssO) that may also be implicated in repair regulation. In this work, we evaluate the effect of ssO on end-joining at DSB sites both in vitro and in cells. Under both conditions, we report that ssO inhibit C-NHEJ through binding to Ku and favor repair by the Lig4-independent microhomology-mediated A-EJ process. Our data bring new clues in the understanding of the cellular response to DNA double-strand breaks
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Choudhury, Sibgat Ahmed. "Role of TRM2RNC1 endo-exonuclease in DNA double strand break repair." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103373.
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DNA double strand breaks (DSB) are the most toxic of all types of DNA lesions. In Saccharomyces cerevisiae, DNA DSBs are predominantly repaired by the homologous recombination repair (HRR) pathway. The initial step of HRR requires extensive processing of DNA ends from the 5' to 3' direction by specific endo-exonuclease(s) (EE) at the DSB sites, but no endo-exonuclease(s) has yet been conclusively determined for such processing of DSBs. S. cerevisiae TRM2/RNC1 is a candidate endo-exonuclease that was previously implicated for its role in the HRR pathway and was also shown to have methyl transferase activity primarily located at its c-terminus.In this dissertation, we provided compelling biochemical and genetic evidence that linked TRM2/RNC1 to the DNA end processing role in HRR. Trm2/Rnc1p purified with a small calmodulin binding peptide (CBP) tag displayed single strand (ss) specific endonuclease and double strand (ds) specific 5' to 3' exonuclease activity characteristic of endo-exonucleases involved in HRR. Intriguingly, purified Trm2/Rnc1p deleted for its C-terminal methyl transferase domain retained its nuclease activity but not the methyl transferase activity indicating that the C-terminal part responsible for its methyl transferase function is not required for its nuclease activity.
Our genetic and functional studies with S. cerevisiae trm2/rnc1 single mutants alone or in combination with other DNA DSB repair mutants after treatment with the DNA damaging drug methyl methane sulfonate (MMS) or IR that is believed to produce DSBs, or with specific induction of DNA DSBs at the MAT locus by HO-endonuclease demonstrated an epistatic relationship of TRM2/RNC1 with the major recombination factor RAD52. These studies suggested that TRM2/RNC1 probably acts at an earlier step than RAD52 in the HRR pathway. The genetic evidence also indicated a possible functional redundancy with the bona fide endo-exonuclease EXO1 in the processing of DNA ends at the DSB sites.
In a recent report, the immuno-purified mouse homologue of TRM2/RNC1 exhibited similar enzymatic properties as the endo-exonucleases involved in HRR. A small molecular inhibitor pentamidine specifically inhibited the nuclease activity of the mouse EE and sensitized various cancer cells to DNA damaging agents commonly used in cancer chemotherapy. We specifically suppressed expression of the mouse EE using small interfering RNA (siRNA) that conferred sensitivity of B16F10 melanoma cells to a variety of DNA damaging drugs often used in cancer treatment. This further validated our earlier claim of the endo-exonuclease as a potential therapeutic target in treating cancer.
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Ku, Chuan-Chih. "TCP6, a regulator in Arabidopsis gametophyte development and DNA damage response." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17892.
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Plants have developed intricate mechanisms to control growth in response to a variety of environmental cues, to compensate its immobility and to survive in both normal and adverse conditions. The TCP proteins are a family of plant-specific, basic helix-loop-helix (bHLH) transcription factors that involve in different aspects in plant growth and developmental control. The Arabidopsis TCP20 has been shown to involve in coordinating cell growth and proliferation, and in growth arrest in response to DNA double-stranded breaks (DSB). In this thesis, the main interest is to examine the function of Arabidopsis TCP6, which shares the highest homology with TCP20, and like TCP20, contains a putative ATM phosphorylation motif that suggests potential involvement in the ATM/ATR-mediated DSB responses. Expressional analysis including transcript measurement and reporter gene tagging demonstrated that TCP6 is expressed in flowers, in particular in the first mitotic event of pollen and ovule/embryo sac development, indicating that TCP6 potentially involves in regulating the mitotic cell cycle during gametophyte development. Yet no gametophytic or fertility-affecting mutant phenotype was observed in the tcp6 single and tcp6/tcp20 double mutants, which may be due to high functional redundancy. The tcp6/tcp20 double mutant seedlings exhibited significantly higher growth performances in true leaf growth compared to wild type when treated with gamma radiation, implying that both functional TCP6 and TCP20 are involved in response to gamma radiation-generated DSBs. The work of this thesis provides the first expressional and functional characterizations of TCP6, with the results suggesting that TCP6 and other class I TCPs play a role in regulating growth under both normal and stress conditions.
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Vasianovich, Yuliya. "Investigating the roles of the Srs2 and Pif1 helicases in DNA double-strand break repair in Saccharomyces cerevisiae." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/17984.
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DNA double strand breaks (DSBs), which may occur during DNA replication or due to the action of genotoxic agents, are extremely dangerous DNA lesions as they can cause chromosomal rearrangements and cell death. Therefore, accurate DSB repair is vital for genome stability and cell survival. Two main mechanisms serve to repair DNA DSBs: non-homologous end joining, which re-ligates DNA ends together, and homologous recombination (HR), which restores broken DNA using homologous sequence as a template for repair. One-ended DSBs are a subject for the specialised HR-dependent repair pathway known as break-induced replication (BIR). At low frequency, DNA breaks can also be healed by telomerase, which normally extends telomeres at natural chromosome ends, but may also add de novo telomeres to DSBs due to their similarity to chromosome ends. De novo telomere addition is a deleterious event, which is effectively inhibited by the nuclear Pif1 (nPif1) helicase phosphorylated at the TLSSAES motif in response to DNA damage. In this study, it is reported that the same regulatory motif of nPif1 is also required for DSB repair via BIR. The requirement of the nPif1 TLSSAES sequence in BIR is dependent on the functional DNA damage response (DDR). Thus, nPif1 phosphorylation by the DDR machinery might mediate the role of nPif1 in BIR. In contrast, the nPif1 regulatory motif is not essential for BIR at telomeres in cells lacking telomerase. These observations indicate that the mechanism of nPif1 function in DSB repair via BIR and in BIR at telomeres might be different. In this work, a protocol for nPif1 pull-down was optimized to reveal the mechanism of the phosphorylation-dependent nPif1 functions in cells undergoing DNA repair, i. e. the mechanism of nPif1-mediated inhibition of de novo telomere addition and promoting DSB repair via BIR. In future, this protocol can be used to dissect the role of nPif1 in DNA repair through the identification of its potential interacting partners. The Srs2 helicase negatively regulates HR via dismantling Rad51 filaments. According to preliminary data from the laboratory of Sveta Makovets, Srs2 also promotes de novo telomere addition at DSBs in a Rad51-dependent manner. The work presented here establishes that Srs2 is dispensable for telomerase-mediated addition of TG1-3 repeats to DSBs. Instead, Srs2 is required for the reconstitution of the complementary DNA strand after telomerase action, thus ensuring the completion of de novo telomere addition. Overall, this study demonstrates that recombination-dependent DSB repair and de novo telomere addition share common regulatory components, i. e. the nPif1 helicase phosphorylated in response to DNA damage and the Srs2 helicase. Phosphorylated nPif1 promotes DSB repair via BIR in addition to its known role in inhibition of telomerase at DSBs, whereas Srs2 uses its well established ability to remove Rad51 from ssDNA to promote the restoration of dsDNA and thus to complete de novo telomere addition.
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Weatherbee, Jessica L. "Exploiting DNA Repair and ER Stress Response Pathways to Induce Apoptosis in Glioblastoma Multiforme: A Dissertation." eScholarship@UMMS, 2008. http://escholarship.umassmed.edu/gsbs_diss/865.
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Glioblastoma multiforme (GBM) is a deadly grade IV brain tumor characterized by a heterogeneous population of cells that are drug resistant, aggressive, and infiltrative. The current standard of care, which has not changed in over a decade, only provides GBM patients with 12-14 months survival post diagnosis. We asked if the addition of a novel endoplasmic reticulum (ER) stress inducing agent, JLK1486, to the standard chemotherapy, temozolomide (TMZ), which induces DNA double strand breaks (DSBs), would enhance TMZ’s efficacy. Because GBMs rely on the ER to mitigate their hypoxic environment and DNA repair to fix TMZ induced DSBs, we reasoned that DSBs occurring during heightened ER stress would be deleterious.
Treatment of GBM cells with TMZ+JLK1486 decreased cell viability and increased cell death due to apoptosis. We found that TMZ+JLK1486 prolonged ER stress induction, as indicated by elevated ER stress marker BiP, ATF4, and CHOP, while sustaining activation of the DNA damage response pathway. This combination produced unresolved DNA DSBs due to RAD51 reduction, a key DNA repair factor. The combination of TMZ+JLK1486 is a potential novel therapeutic combination and suggests an inverse relationship between ER stress and DNA repair pathways.
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Weatherbee, Jessica L. "Exploiting DNA Repair and ER Stress Response Pathways to Induce Apoptosis in Glioblastoma Multiforme: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/865.
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Glioblastoma multiforme (GBM) is a deadly grade IV brain tumor characterized by a heterogeneous population of cells that are drug resistant, aggressive, and infiltrative. The current standard of care, which has not changed in over a decade, only provides GBM patients with 12-14 months survival post diagnosis. We asked if the addition of a novel endoplasmic reticulum (ER) stress inducing agent, JLK1486, to the standard chemotherapy, temozolomide (TMZ), which induces DNA double strand breaks (DSBs), would enhance TMZ’s efficacy. Because GBMs rely on the ER to mitigate their hypoxic environment and DNA repair to fix TMZ induced DSBs, we reasoned that DSBs occurring during heightened ER stress would be deleterious.
Treatment of GBM cells with TMZ+JLK1486 decreased cell viability and increased cell death due to apoptosis. We found that TMZ+JLK1486 prolonged ER stress induction, as indicated by elevated ER stress marker BiP, ATF4, and CHOP, while sustaining activation of the DNA damage response pathway. This combination produced unresolved DNA DSBs due to RAD51 reduction, a key DNA repair factor. The combination of TMZ+JLK1486 is a potential novel therapeutic combination and suggests an inverse relationship between ER stress and DNA repair pathways.
Book chapters on the topic "Double-Stranded DNA Breaks"
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Blitzblau, Hannah G., and Andreas Hochwagen. "Genome-Wide Detection of Meiotic DNA Double-Strand Break Hotspots Using Single-Stranded DNA." In Methods in Molecular Biology, 47–63. Totowa, NJ: Humana Press, 2011. http://dx.doi.org/10.1007/978-1-61779-129-1_4.
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Short, Susan. "Radiotherapy and radiosurgery for brain tumours." In Oxford Textbook of Neurological Surgery, edited by Ramez W. Kirollos, Adel Helmy, Simon Thomson, and Peter J. A. Hutchinson, 141–48. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780198746706.003.0011.
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Following surgery fractionated radiotherapy is standard treatment for high-grade gliomas. The place for radiotherapy in low-grade gliomas is more open to debate. Radiotherapy works by causing double stranded DNA breaks, there are two DNA repair pathways in mammalian cells, tumour cells are less able to repair DNA damage caused by radiotherapy than normal cells, thus radiotherapy is usually delivered in fractions. Conformal beam and intensity-modulated radiotherapy techniques can be used to optimize the distribution of the radiation and protect organs at risk. Brachytherapy, gamma knife, boron neutron capture, and proton beam therapy are other techniques in development or with indications for use in certain situations. The side effects of radiotherapy include fatigue, hair loss, pseudoprogression, which can be difficult to distinguish from tumour recurrence and induced secondary tumours.
Conference papers on the topic "Double-Stranded DNA Breaks"
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Weng, Mao Wen, Yi Zheng, Vijay P. Jasti, Elise Champeil, Maria Tomasz, Yin sheng Wang, Ashis K. Basu, and Moon Shong Tang. "Abstract 1967: UvrABC excision of interstrand crosslink mitomycin C-DNA lesion induces double-stranded DNA breaks." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-1967.
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