• Title/Summary/Keyword: DSBs

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PATHWAYS AND GENES OF DNA DOUBLE-STRAND BREAK REPAIR ASSOCIATED WITH HEAD AND NECK CANCER (DNA 이중나선파손의 수복 과정과 이와 연관된 두경부암 발생 유전자)

  • Oh, Jung-Hwan;Lee, Deok-Won;Ryu, Dong-Mok
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.35 no.1
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    • pp.1-6
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    • 2009
  • DNA double-strand breaks (DSBs) occur commonly in the all living and in cycling cells. They constitute one of the most severe form of DNA damage, because they affect both strand of DNA. DSBs result in cell death or a genetic alterations including deletion, loss of heterozygosity, translocation, and chromosome loss. DSBs arise from endogenous sources like metabolic products and reactive oxygen, and also exogenous factors like ionizing radiation. Defective DNA DSBs can lead to toxicity and large scale sequence rearrangement that can cause cancer and promote premature aging. There are two major pathways for their repair: homologous recombination(HR) and non-homologous end-joining(NHEJ). The HR pathway is a known "error-free" repair mechanism, in which a homologous sister chromatid serves as a template. NHEJ, on the other hand, is a "error-prone" pathway, in which the two termini of the broken DNA molecule are used to form compatible ends that are directly ligated. This review aims to provide a fundamental understanding of how HR and NHEJ pathways operate, cause genome instability, and what kind of genes during the pathways are associated with head and neck cancer.

Ku complex suppresses recombination in the absence of MRX activity during budding yeast meiosis

  • Yun, Hyeseon;Kim, Keunpil
    • BMB Reports
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    • v.52 no.10
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    • pp.607-612
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    • 2019
  • During meiosis, programmed double-strand breaks (DSBs) are repaired via recombination pathways that are required for faithful chromosomal segregation and genetic diversity. In meiotic progression, the non-homologous end joining (NHEJ) pathway is suppressed and instead meiotic recombination initiated by nucleolytic resection of DSB ends is the major pathway employed. This requires diverse recombinase proteins and regulatory factors involved in the formation of crossovers (COs) and non-crossovers (NCOs). In mitosis, spontaneous DSBs occurring at the G1 phase are predominantly repaired via NHEJ, mediating the joining of DNA ends. The Ku complex binds to these DSB ends, inhibiting additional DSB resection and mediating end joining with Dnl4, Lif1, and Nej1, which join the Ku complex and DSB ends. Here, we report the role of the Ku complex in DSB repair using a physical analysis of recombination in Saccharomyces cerevisiae during meiosis. We found that the Ku complex is not essential for meiotic progression, DSB formation, joint molecule formation, or CO/NCO formation during normal meiosis. Surprisingly, in the absence of the Ku complex and functional Mre11-Rad50-Xrs2 (MRX) complex, a large portion of meiotic DSBs was repaired via the recombination pathway to form COs and NCOs. Our data suggested that Ku complex prevents meiotic recombination in the elimination of MRX activity.

Epidermal Growth Factor Receptor-Related DNA Repair and Radiation-Resistance Regulatory Mechanisms: A Mini-Review

  • Bai, Jing;Guo, Xiao-Guang;Bai, Xiao-Ping
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.10
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    • pp.4879-4881
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    • 2012
  • Epidermal growth factor receptor (EGFR) overexpression is associated with resistance to chemotherapy and radiotherapy. The EGFR modulates DNA repair after radiation-induced damage through an association with the catalytic subunit of DNA protein kinase. DNA double-strand breaks (DSBs) are the most lethal type of DNA damage induced by ionizing radiation, and non-homologous end joining is the predominant pathway for repair of radiation-induced DSBs. Some cell signaling pathways that respond to normal growth factors are abnormally activated in human cancer. These pathways also invoke the cell survival mechanisms that lead to resistance to radiation. The molecular connection between the EGFR and its control over DNA repair capacity appears to be mediated by one or more signaling pathways downstream of this receptor. The purpose of this mini-review was not only to highlight the relation of the EGFR signal as a regulatory mechanism to DNA repair and radiation resistance, but also to provide clues to improving existing radiation resistance through novel therapies based on the above-mentioned mechanism.

DNA Double-Strand Breaks Serve as a Major Factor for the Expression of Arabidopsis Argonaute 2

  • Lee, Sungbeom;Chung, Moon-Soo;Lee, Gun Woong;Chung, Byung Yeoup
    • Journal of Radiation Industry
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    • v.10 no.4
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    • pp.243-248
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    • 2016
  • Argonaute 2 (AtAGO2) is a well characterized effector protein in Arabidopsis for its functionalities associated with DNA double-strand break (DSB)-induced small RNAs (diRNAs) and for its inducible expression upon ${\gamma}$-irradiation. However, its transcriptional regulation depending on the recovery time after the irradiation and on the specific response to DSBs has been poorly understood. We analyzed the 1,313 bp promoter sequence of the AtAGO2 gene ($1.3kb_{pro}$) to characterize the transcriptional regulation of AtAGO2 at various recovery times after ${\gamma}$-irradiation. A stable transformant harboring $1.3kb_{pro}$ fused with GUS gene showed that the AtAGO2 is highly expressed in response to ${\gamma}$-irradiation, after which the expression of the gene is gradually decreased until 5 days of DNA damage recovery. We also confirm that the AtAGO2 expression patterns are similar to that of ${\gamma}$-irradiation after the treatments of radiomimetic genotoxins (bleomycin and zeocin). However, methyl methanesulfonate and mitomycin C, which are associated with the inhibition of DNA replication, do not induce the expression of the AtAGO2, suggesting that the expression of the AtAGO2 is closely related with DNA DSBs rather than DNA replication.

Identification of Meiotic Recombination Intermediates in Saccharomyces cerevisiae (효모 감수분열과정에서의 유전자 재조합 기전 특이적 DNA 중간체의 구조 변화)

  • Sung, Young Jin;Yoon, Sang Wook;Kim, Keun Pil
    • Korean Journal of Microbiology
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    • v.49 no.1
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    • pp.1-7
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    • 2013
  • During meiosis, genetic recombinants are formed by homologous recombination accompanying with the programmed double-strand breaks (DSBs) and strand exchanges between homologous chromosomes. The mechanism is generated by recombination intermediates such as single-end invasions (SEIs) and double-Holliday junctions (dHJs), and followed by crossover (CO) or non-crossover (NCO) products. Our study was focused on the analysis of meiotic recombination intermediates (DSBs, SEIs, and dHJs) and final recombination products (CO and NCO). We identified these meiotic recombination intermediates using DNA physical analysis under HIS4LEU2 "hot spot" system in budding yeast, Saccharomyces cerevisiae. For DNA physical analysis, when the hot spot locus is recognized by restriction enzyme from synchronous meiotic cells, the fragmented DNA that are forming recombination intermediates can be detected and quantified through Southern hybridization analysis. Our study suggests that this system can analyze the structural change of recombination intermediates during DSB-SEI transition, double-Holiday junctions and crossover/non-crossover products in meiosis.

Knocking Down Nucleolin Expression Enhances the Radiosensitivity of Non-Small Cell Lung Cancer by Influencing DNA-PKcs Activity

  • Xu, Jian-Yu;Lu, Shan;Xu, Xiang-Ying;Hu, Song-Liu;Li, Bin;Qi, Rui-Xue;Chen, Lin;Chang, Joe Y.
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.8
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    • pp.3301-3306
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    • 2015
  • Nucleolin (C23) is an important anti-apoptotic protein that is ubiquitously expressed in exponentially growing eukaryotic cells. In order to understand the impact of C23 in radiation therapy, we attempted to investigate the relationship of C23 expression with the radiosensitivity of human non-small cell lung cancer (NSCLC) cells. We investigated the role of C23 in activating the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), which is a critical protein for DNA double-strand breaks (DSBs) repair. As a result, we found that the expression of C23 was negatively correlated with the radiosensitivity of NSCLC cell lines. In vitro clonogenic survival assays revealed that C23 knockdown increased the radiosensitivity of a human lung adenocarcinoma cell line, potentially through the promotion of radiation-induced apoptosis and adjusting the cell cycle to a more radiosensitive stage. Immunofluorescence data revealed an increasing quantity of ${gamma}$-H2AX foci and decreasing radiation-induced DNA damage repair following knockdown of C23. To further clarify the mechanism of C23 in DNA DSBs repair, we detected the expression of DNA-PKcs and C23 proteins in NSCLC cell lines. C23 might participate in DNA DSBs repair for the reason that the expression of DNA-PKcs decreased at 30, 60, 120 and 360 minutes after irradiation in C23 knockdown cells. Especially, the activity of DNA-PKcs phosphorylation sites at the S2056 and T2609 was significantly suppressed. Therefore we concluded that C23 knockdown can inhibit DNA-PKcs phosphorylation activity at the S2056 and T2609 sites, thus reducing the radiation damage repair and increasing the radiosensitivity of NSCLC cells. Taken together, the inhibition of C23 expression was shown to increase the radiosensitivity of NSCLC cells, as implied by the relevance to the notably decreased DNA-PKcs phosphorylation activity at the S2056 and T2609 clusters. Further research on targeted C23 treatment may promote effectiveness of radiotherapy and provide new targets for NSCLC patients.

Shear bond strength of dentin bonding agents cured with a plasma arc curing light (전단접착강도와 관련된 Plasma Arc Curing Light의 중합효율평가)

  • Kwon, Young-Chul;Kim, Sun-Young;Chung, Sae-Joon;Han, Young-Chul;Lee, In-Bog;Son, Ho-Hyun;Um, Chung-Moon;Cho, Byeong-Hoon
    • Proceedings of the KACD Conference
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    • 2008.05a
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    • pp.213-223
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    • 2008
  • The objective of this study was to compare dentin shear bond strength (DSBS) of dentin bonding agents (DBAs) cured with a plasma arc (PAC) light curing unit (LCU) and those cured with a light emitting diode (LED) LCU. Optical properties were also analyzed for Elipar freelight 2 (3M ESPE); LED LCU, Apollo 95E (DMT Systems); PAC LCU and VIP Junior (Bisco); Halogen LCU. The DBAs used for DSBS test were Scotchbond Multipurpose (3M ESPE), Singlebond 2 (3M ESPE) and Clearfil SE Bond (Kuraray). After DSBS testing, fractured specimens were analyzed for failure modes with SEM. The total irradiance and irradiance between 450 nm and 490 nm of the LCUs were different. LED LCU showed narrow spectral distribution around its peak at 462 nm whereas PAC and Halogen LCU showed a broad spectrum. There were no significant differences in mean shear bond strength among different LCUs (P > 0.05) but were significant differences among different DBAs (P < 0.001).

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Shear bond strength of dentin bonding agents cured with a plasma arc curing light (전단접착강도와 관련된 Plasma Arc Curing Light의 중합효율평가)

  • Kwon, Young-Chul;Kim, Sun-Young;Chung, Sae-Joon;Han, Young-Chul;Lee, In-Bog;Son, Ho-Hyun;Um, Chung-Moon;Cho, Byeong-Hoon
    • Restorative Dentistry and Endodontics
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    • v.33 no.3
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    • pp.213-223
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    • 2008
  • The objective of this study was to compare dentin shear bond strength (DSBS) of dentin bonding agents (DBAs) cured with a plasma arc (PAC) light curing unit (LCU) and those cured with a light emitting diode (LED) LCU. Optical properties were also analyzed for Elipar freelight 2 (3M ESPE); LED LCU, Apollo 95E (DMT Systems); PAC LCU and VIP Junior (Bisco); Halogen LCU. The DBAs used for DSBS test were Scotchbond Multipurpose (3M ESPE), Singlebond 2 (3M ESPE) and Clearfil SE Bond (Kuraray). After DSBS testing, fractured specimens were analyzed for failure modes with SEM. The total irradiance and irradiance between 450 nm and 490 nm of the LCUs were different. LED LCU showed narrow spectral distribution around its peak at 462 nm whereas PAC and Halogen LCU showed a broad spectrum. There were no significant differences in mean shear bond strength among different LCUs (P > 0.05) but were significant differences among different DBAs (P < 0.001)

Electronic Properties and Conformation Analysis of π-Conjugated Distyryl Benzene Derivaties

  • Kim, Cheol-Ju
    • Bulletin of the Korean Chemical Society
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    • v.23 no.2
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    • pp.330-336
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    • 2002
  • A quantum-chemical investigation on the conformations and electronic properties of bis[2-{2-methoxy-4,6-di(t-butyl)phenyl}ethenyl]benzenes (MBPBs) as building block for ${\pi}$-conjugate polymer are performed in order to display the effects of t-butyl and methoxy group substitution and of kink(ortho and meta) linkage. The conjugation length of the polymers can be controlled by substituents and kink linkages of backbone. Structures for the molecules, o-, m-, and p-MBPBs as well as unsubstituted o-, m-, and p-DSBs were fully optimized by using semiempirical AM1, PM3 methods, and ab initio HF method with 3-21G(d) basis set. The potential energy curves with respect to the change of single torsion angle are obtained by using semiempirical methods and ab initio HF/3-21G(d) basis set. The curves are similar shape in the molecules with respect to the position of vinylene groups. It is shown that the conformations of the molecules are compromised between the steric repulsion interaction and the degree of the conjugation. Electronic properties of the molecules were obtained by applying the optimized structures and geometries to the ZINDO/S method. ZINDO/S analysis performed on the geometries obtained by AM1 method and HF/3-21G(d) level is reported. The absorption wavelength on the geometries obtained by AM1 method is much longer than that by HF/3-21G(d) level. The absorption wavelength of MBPBs are red shifted with comparison to that of corresponding DSBs in the same torsion angle because of electron donating substituents. The absorption wavelength of isomers with kink(orth and meta) linkage is shorter than that of para linkage.

Hop2 and Sae3 Are Required for Dmc1-Mediated Double-Strand Break Repair via Homolog Bias during Meiosis

  • Cho, Hong-Rae;Kong, Yoon-Ju;Hong, Soo-Gil;Kim, Keun Pil
    • Molecules and Cells
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    • v.39 no.7
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    • pp.550-556
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    • 2016
  • During meiosis, exchange of DNA segments occurs between paired homologous chromosomes in order to produce recombinant chromosomes, helping to increase genetic diversity within a species. This genetic exchange process is tightly controlled by the eukaryotic RecA homologs Rad51 and Dmc1, which are involved in strand exchange of meiotic recombination, with Rad51 participating specifically in mitotic recombination. Meiotic recombination requires an interaction between homologous chromosomes to repair programmed double-strand breaks (DSBs). In this study, we investigated the budding yeast meiosis-specific proteins Hop2 and Sae3, which function in the Dmc1-dependent pathway. This pathway mediates the homology searching and strand invasion processes. Mek1 kinase participates in switching meiotic recombination from sister bias to homolog bias after DSB formation. In the absence of Hop2 and Sae3, DSBs were produced normally, but showed defects in the DSB-to-single-end invasion transition mediated by Dmc1 and auxiliary factors, and mutant strains failed to complete proper chromosome segregation. However, in the absence of Mek1 kinase activity, Rad51-dependent recombination progressed via sister bias in the $hop2{\Delta}$ or $sae3{\Delta}$ mutants, even in the presence of Dmc1. Thus, Hop2 and Sae3 actively modulate Dmc1-dependent recombination, effectively progressing homolog bias, a process requiring Mek1 kinase activation.