Jiying Sun

Hiroshima University, Hirosima, Hiroshima, Japan

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Publications (26)113.05 Total impact

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    ABSTRACT: The reorganization of damaged chromatin plays an important role in the regulation of the DNA damage response. A recent study revealed the presence of 2 vertebrate H2A.Z isoforms, H2A.Z-1 and H2A.Z-2. However, the roles of the vertebrate H2A.Z isoforms are still unclear. Thus, in this study we examined the roles of the vertebrate H2A.Z isoforms in chromatin reorganization after the induction of DNA double-strand breaks (DSBs).
    International journal of radiation oncology, biology, physics 07/2014; 89(4):736-44. · 4.59 Impact Factor
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    ABSTRACT: Oxidative stress contributes to both aging and tumorigenesis. The transcription factor Bach1, a regulator of oxidative stress response, augments oxidative stress by repressing the expression of heme oxygenase-1 (HO-1) gene (Hmox1) and suppresses oxidative stress-induced cellular senescence by restricting the p53 transcriptional activity. Here we investigated the lifelong effects of Bach1 deficiency on mice. Bach1-deficient mice showed longevity similar to wild-type mice. Although HO-1 was upregulated in the cells of Bach1-deficient animals, the levels of ROS in Bach1-deficient HSCs were comparable to those in wild-type cells. Bach1 (-/-); p53 (-/-) mice succumbed to spontaneous cancers as frequently as p53-deficient mice. Bach1 deficiency significantly altered transcriptome in the liver of the young mice, which surprisingly became similar to that of wild-type mice during the course of aging. The transcriptome adaptation to Bach1 deficiency may reflect how oxidative stress response is tuned upon genetic and environmental perturbations. We concluded that Bach1 deficiency and accompanying overexpression of HO-1 did not influence aging or p53 deficiency-driven tumorigenesis. Our results suggest that it is useful to target Bach1 for acute injury responses without inducing any apparent deteriorative effect.
    Oxidative medicine and cellular longevity. 01/2014; 2014:757901.
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    ABSTRACT: Homologous recombination plays essential roles in mitotic DNA double strand break (DSB) repair and meiotic genetic recombination. In eukaryotes, RAD51 promotes the central homologous-pairing step during homologous recombination, but is not sufficient to overcome the reaction barrier imposed by nucleosomes. RAD54, a member of the ATP-dependent nucleosome remodeling factor family, is required to promote the RAD51-mediated homologous pairing in nucleosomal DNA. In higher eukaryotes, most nucleosomes form higher-ordered chromatin containing the linker histone H1. However, the mechanism by which RAD51/RAD54-mediated homologous pairing occurs in higher-ordered chromatin has not been elucidated. In this study, we found that a histone chaperone, Nap1, accumulates on DSB sites in human cells, and DSB repair is substantially decreased in Nap1-knockdown cells. We determined that Nap1 binds to RAD54, enhances the RAD54-mediated nucleosome remodeling by evicting histone H1, and eventually stimulates the RAD51-mediated homologous pairing in higher-ordered chromatin containing histone H1.
    Scientific Reports 01/2014; 4:4863. · 5.08 Impact Factor
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    ABSTRACT: Genetic information encoded in chromosomal DNA is challenged by intrinsic and exogenous sources of DNA damage. DNA double-strand breaks (DSBs) are extremely dangerous DNA lesions. RAD51 plays a central role in homologous recombinational DSB repair, by facilitating the recombination of damaged DNA with intact DNA in eukaryotes. RAD51 accumulates at sites containing DNA damage to form nuclear foci. However, the mechanism of RAD51 accumulation at sites of DNA damage is still unclear. Posttranslational modifications of proteins, such as phosphorylation, acetylation and ubiquitination, play a role in the regulation of protein localization and dynamics. Recently, the covalent binding of small ubiquitin-like modifier (SUMO) proteins to target proteins, termed SUMOylation, at sites containing DNA damage has been determined to play a role in the regulation of the DNA damage response. Here we show that the SUMOylation E2, UBC9, and E3, PIAS1 and PIAS4 enzymes are required for RAD51 accretion at sites containing DNA damage in human cells. Moreover, we identified a SUMO-interacting motif (SIM) in RAD51, which is necessary for RAD51 accumulation at sites of DNA damage. These findings suggest that the SUMO-SIM system plays an important role in DNA repair, through the regulation of RAD51 dynamics.
    Journal of Cell Science 09/2013; · 5.88 Impact Factor
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    ABSTRACT: Poly(ADP-ribose) polymerase (PARP) plays a critical role in responding to DNA damage, by activating DNA repair pathways responsible for cellular survival. PARP inhibition is used to treat certain solid cancers, such as breast and ovarian cancers. However, its effectiveness with other solid cancers, such as esophageal squamous cell carcinoma (ESCC), has not been clarified. We evaluated the effects of PARP inhibition on the survival of human esophageal cancer cells, with a special focus on the induction and repair of DNA double-strand breaks. The effects were monitored by colony formation assays and DNA damage responses, with immunofluorescence staining of γH2AX and RAD51. We found that PARP inhibition synergized with cisplatin, and the cells were highly sensitive, in a similar manner to the combination of cisplatin and 5-fluorouracil (5-FU). Comparable increases in RAD51 foci formation were observed after each combinational treatment with cisplatin and either 3-aminobenzamide (3-AB) or 5-FU in three human esophageal cancer cell lines, TE11, TE14 and TE15. In addition, decreasing the amount of RAD51 by RNA interference rendered the TE11 cells even more hypersensitive to these combinational treatments. Our findings suggested that the homologous recombinational repair pathway may be involved in the synergism between cisplatin and either 3-AB or 5-FU, and that 3-AB and 5-FU may similarly modify the cisplatin-induced DNA damage to types requiring the recruitment of RAD51 proteins for their repair. Understanding these mechanisms could be useful for improving the clinical outcome of ESCC patients, who suffer from aggressive diseases that presently lack effective treatment options. This article is protected by copyright. All rights reserved.
    Cancer Science 09/2013; · 3.48 Impact Factor
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    ABSTRACT: 5-Fluorouracil (5-FU) is one of the most well established chemotherapeutic agents in the treatment of esophageal cancer. Ribonucleotide reductase M1 (RRM-1) is the rate‑limiting enzyme in de novo DNA synthesis, and has been considered to play an important role in the 5-FU metabolic pathway. However, the means by which RRM-1 participates in the anticancer effects of 5-FU and cisplatin (CDDP) have not been well studied. Here, we show that RRM-1 significantly contributes to the induction of DNA damage by 5-FU in esophageal cancer cell lines. An assay of γ-H2AX focus formation, a marker of DNA damage, after 5-FU treatment revealed good correlation with the levels of RRM-1 protein expression. Moreover, the increased sensitivity and RAD51 focus formation induced by the combination treatment of 5-FU and CDDP were significantly repressed by RRM-1 depletion. These results suggest that RRM-1 is involved not only in the induction of DNA damage by 5-FU but also in the synergistic cytotoxic effect in the combination therapy of 5-FU and CDDP.
    International Journal of Oncology 04/2013; · 2.66 Impact Factor
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    ABSTRACT: The analysis of dicentric chromosomes in human peripheral blood lymphocytes (PBLs) by Giemsa staining is the most established method for biological dosimetry. However, this method requires a well-trained person because of the difficulty in detecting aberrations rapidly and accurately. Here, we applied a fluorescence in situ hybridization (FISH) technique, using telomere and centromere peptide nucleic acid (PNA) probes, to solve the problem of biological dosimetry in radiation emergency medicine. A comparison by a well-trained observer found that FISH analysis of PBLs for the dose estimation was more accurate than the conventional Giemsa analysis, especially in samples irradiated at high doses. These results show that FISH analysis with centromeric/telomeric PNA probes could become the standard method for biological dosimetry in radiation emergency medicine.
    Radiation Research 04/2012; 177(5):533-8. · 2.70 Impact Factor
  • Satoshi Tashiro, Jiying Sun
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    ABSTRACT: Ionizing radiation has been shown to induce various types of chromosomal DNA damages. Among these DNA damages, DNA double strand breaks(DSBs) are the most severe damages resulting in cell death or chromosome abnormalities. Proteins associated with DNA repair, such as phosphorylated form of histone H2AX, a histone variant of H2A, and a DNA recombinase RAD51, has been shown to form radiation-induced repair foci at sites containing DNA damage. Reorganization of damaged chromatin by protein modifications or exchange of histones has been shown to play an important role in the formation of radiation induced repair foci.
    Nippon rinsho. Japanese journal of clinical medicine 03/2012; 70(3):383-7.
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    ABSTRACT: The meiosis-specific synaptonemal complex protein SYCP3 has been reported to be aberrantly expressed in tumours. However, in contrast to its well-defined function in meiosis, its possible role in mitotic cells is entirely unknown. Here, we show that SYCP3 is expressed in a range of primary tumours and that it impairs chromosomal integrity in mitotic cells. Expression of SYCP3 inhibits the homologous recombination (HR) pathway mediated by RAD51, inducing hypersensitivity to DNA-damaging agents such as a poly(ADP-ribose) polymerase (PARP) inhibitor and chromosomal instability. SYCP3 forms a complex with BRCA2 and inhibits its role in HR. These findings highlight a new mechanism for chromosomal instability in cancer and extend the range of PARP-inhibitor sensitive tumours to those expressing SYCP3.
    EMBO Reports 11/2011; 13(1):44-51. · 7.19 Impact Factor
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    ABSTRACT: Chromosome translocations induced by DNA damaging agents, such as ionizing radiation and certain chemotherapies, alter genetic information resulting in malignant transformation. Abrogation or loss of the ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, increases the incidence of chromosome translocations. However, how ATM protects cells from chromosome translocations is still unclear. Chromosome translocations involving the MLL gene on 11q23 are the most frequent chromosome abnormalities in secondary leukemias associated with chemotherapy employing etoposide, a topoisomerase II poison. Here we show that ATM deficiency results in the excessive binding of the DNA recombination protein RAD51 at the translocation breakpoint hotspot of 11q23 chromosome translocation after etoposide exposure. Binding of Replication protein A (RPA) and the chromatin remodeler INO80, which facilitate RAD51 loading on damaged DNA, to the hotspot were also increased by ATM deficiency. Thus, in addition to activating DNA damage signaling, ATM may avert chromosome translocations by preventing excessive loading of recombinational repair proteins onto translocation breakpoint hotspots.
    PLoS ONE 01/2010; 5(10):e13554. · 3.53 Impact Factor
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    ABSTRACT: Oxidative stress has been implicated in tissue damage from traumatic brain injury. Heme oxygenase-1 (HO-1) is an inducible enzyme that degrades prooxidant heme to radical-scavenging biliverdin/bilirubin in order to protect cells from oxidative stress. Although HO-1 is induced after induction of brain damage, the regulatory mechanism of HO-1 in the brain is still unclear. Bach1 is a transcriptional repressor of the HO-1 gene, and plays a critical role in tissue protection from oxidative stress by reperfusion injury of the myocardium. In this study, we examined the role of Bach1 in HO-1 regulation of the various brain sites by investigating the expression of Bach1 and HO-1 in brain tissues of mice bearing Bach1-deficient (Bach1(-/-)) or wild-type (Bach1(+/+)) genes. While the expression levels of Bach1 mRNA in the olfactory bulb were significantly higher than other brain areas, those at the cortex showed the lowest activity. Bach1(-/-) mice showed significantly higher HO-1 mRNA expression levels than Bach1(+/+) mice in all brain sites studied. Moreover, higher induction of HO-1 was observed around damaged tissues after cold injury in Bach1(-/-) than Bach1(+/+) mice. Thus, Bach1 plays an important role in regulating the constitutive and inducible expression levels of HO-1 in the brain. Although a significantly higher level of HO-1 was observed in Bach1(-/-) than Bach1(+/+) mice, genetic ablation of the Bach1 gene failed to show any tissue protective effect after cold injury was inflicted on the cortex.
    Neuroscience Letters 09/2008; 440(2):160-5. · 2.03 Impact Factor
  • Satoshi Tashiro, Jiying Sun
    Nippon rinsho. Japanese journal of clinical medicine 02/2007; 65 Suppl 1:105-8.
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    ABSTRACT: BACH2 is a B-cell-specific transcription repressor and is also know as a tumor suppressor in B cell malignancy. Expression of BACH2 is induced in BCR-ABL positive lymphoid cell lines including BV173 by imatinib, a molecular targeting agent for the treatment of chronic myeloid leukemia (CML). Here we show that the activity of the BACH2 gene is related to the nuclear positioning of the gene loci. We examined the spatial association of the BACH2 gene with the centromeric heterochromatin, a transcriptionally repressive subnuclear compartment, by comparing cells with low (BV173 and K562) and high (NAMALWA) levels of BACH2 mRNA. The BACH2 gene was located closer to the centromeric heterochromatin in BV173 and K562 cells as compared to NAMALWA cells. In BV173 cells, the BACH2-centromere distance increased after imatinib treatment to levels similar to those in NAMALWA cells. We also found that diethylmaleate, an oxidative stressor, enhanced the antiproliferative effect of imatinib in only BV173 cells. Since BACH2 induces apoptosis by oxidative stress, these observations suggest that down-regulation of the BACH2 gene through the interaction with centromeric heterochromatin would take part in leukomogenesis of BCR-ABL positive lymphoid leukemia.
    Genes Chromosomes and Cancer 02/2007; 46(1):67-74. · 3.55 Impact Factor
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    ABSTRACT: To identify erythroid-specific heme-regulated genes, we performed differential expression analysis between wild-type and heme-deficient erythroblasts, which had been prepared from wild-type and erythroid-specific delta-aminolevulinate synthase-null mouse ES cells, respectively. Among 8737 clones on cDNA array, 40 cDNA clones, including 34 unknown ESTs, were first selected by their high expression profiles in wild-type erythroblasts, and evaluated further for their erythroid-lineage specificity, expression in hematopoietic tissues in vivo, and heme-dependent expression, which yielded 11, 4, and 4 genes, respectively. Because of the selection strategy employed, the final 4 were considered as the newly identified erythroid-specific heme-regulated genes. These 4 genes were uncoupling protein 2, nucleolar spindle-associated protein, cellular nucleic acid-binding protein, and a novel acetyltransferase-like protein. These findings thus suggest that heme may regulate a wide variety of hitherto unrecognized genes, and further analysis of these genes may clarify their role in erythroid cell differentiation.
    Biochemical and Biophysical Research Communications 03/2006; 340(1):105-10. · 2.41 Impact Factor
  • Kazuhiko Igarashi, Jiying Sun
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    ABSTRACT: Heme--as a prosthetic group of proteins required for oxygen transport and storage, respiration, and biosynthetic pathways--is essential for practically all forms of life. Additionally, the degradation products of heme (i.e., carbon monoxide, biliverdin, and bilirubin) produced by the enzymatic actions of heme oxygenase (HO) and biliverdin reductase, possess various biological activities in vivo. In mammalian cells, heme also functions as an intracellular regulator of gene expression by virtue of its ability to bind to Bach1, a transcription factor that functions in association with small Maf proteins. Normally, such complexes function as repressors by binding to specific target sequences, the Maf recognition element (MARE), within enhancers of genes encoding proteins such as HO-1 and beta-globin. By binding to Bach1, heme induces selective removal of the repressor from the gene enhancers permitting subsequent occupancy of the MAREs by activators that, interestingly, also contain small Maf proteins. Thus small Maf proteins play dual functions in gene expression: complexes with Bach1 repress MARE-dependent gene expression, whereas heterodimers with NF-E2 p45 or related factors (Nrf1, Nrf2, and Nrf3) activate MARE-driven genes. By modulating the equilibrium of the small Maf heterodimer network, heme regulates expression of the cytoprotective enzyme HO-1 during the stress response and of beta-globin during erythroid differentiation. Implications of such heme-regulated gene expression in human diseases including atherosclerosis are discussed.
    Antioxidants and Redox Signaling 01/2006; 8(1-2):107-18. · 7.19 Impact Factor
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    ABSTRACT: The expression of heme oxygenase-1 (HO-1) is regulated by E1 and E2 enhancers, both of which contain multiple Maf recognition elements (MAREs). In living cells, MAREs are bound by Bach1/MafK heterodimers, hence maintaining a quiescent state of the HO-1 gene (hmox-1). However, in transient transfection assays, they act as transcriptional enhancers. Therefore MAREs may manifest their function only in a chromatin environment. By using NIH3T3 cell pools stably transfected with EGFP reporter genes driven by the wild-type or mutated E2 enhancer, we demonstrate that the E2 MAREs function as transcriptional silencers depending on the binding of Bach1/MafK heterodimer in vivo only in a chromatin environment. After cadmium treatment, they switched into transcriptional enhancers. Surprisingly, single MARE site did not exhibit such function. Furthermore, by using DNase I hypersensitivity assay, we demonstrate that simple chromatin condensations were not involved in the Bach1-mediated repression. We conclude that, in a chromatin environment, the E2 MAREs function as transcriptional silencers depending on binding of Bach1/MafK heterodimer.
    Antioxidants and Redox Signaling 01/2006; 8(1-2):60-7. · 7.19 Impact Factor
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    ABSTRACT: Both nuclear factor erythroid 2 45 kDa subunit (p45) and BTB and CNC homolog 1 (Bach) transcription factors can form dimers with one of the small Maf proteins, and these heterodimers bind to the musculoaponeurotic fibrosarcoma oncogene (Maf) recognition element (MARE). MARE is known to act as a critical cis-regulatory element of erythroid and megakaryocytic genes. Although detailed analyses of p45-null mutant mice and small maf compound mutant mice revealed that these factors are both critical for platelet production, the functional contributions of Bach1 and the relationship or redundancy between Bach1 and p45 in megakaryocytes remain to be clarified. To address these issues, we generated transgenic lines of mice bearing human BACH1 cDNA under the control of the GATA-1 locus hematopoietic regulatory domain. The transgenic mouse lines showed significant thrombocytopenia associated with impaired maturation of the megakaryocytes, and they developed myelofibrosis. The megakaryocytes in the transgenic mice exhibited reduced proplatelet formation, and the modal ploidy class of megakaryocytes was 2N, indicating the impairment of endomitosis. Transcription of the p45 target genes was down-regulated and we indeed found that BACH1 binds to the thromboxane synthase gene, one of the target genes for p45 in megakaryocytes. These findings thus provide evidence that BACH1 acts as a transcriptional repressor in the regulation of MARE-dependent genes in megakaryocytes.
    Blood 05/2005; 105(8):3100-8. · 9.78 Impact Factor
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    ABSTRACT: The transcriptional factor Bach1 forms a heterodimer with small Maf family, and functions as a repressor of the Maf recognition element (MARE) in vivo. To investigate the involvement of Bach1 in the heme-dependent regulation of the expression of the alpha-globin gene, human erythroleukemia K562 cells were cultured with succinylacetone (SA), a heme biosynthetic inhibitor, and the level of alpha-globin mRNA was examined. A decrease of alpha-globin mRNA was observed in SA-treated cells, which was restored by the addition of hemin. The heme-dependent expression of alpha-globin occurred at the transcriptional level since the expression of human alpha-globin gene promoter-reporter gene containing hypersensitive site-40 (HS-40) was decreased when K562 cells were cultured with SA. Hemin treatment restored the decrease of the promoter activity by SA. The regulation of the HS-40 activity by heme was dependent on the NF-E2/AP-1 (NA) site, which is similar to MARE. The NA site-binding activity of Bach1 in K562 increased upon SA-treatment, and the increase was diminished by the addition of hemin. The transient expression of Bach1 and mutated Bach1 lacking CP motifs suppressed the HS-40 activity, and cancellation of the repressor activity by hemin was observed when wild-type Bach1 was expressed. The expression of NF-E2 strengthened the restoration of the Bach1-effect by hemin. Interestingly, nuclear localization of Bach1 increased when cells were treated with SA, while hemin induced the nuclear export of Bach1. These results indicated that heme plays an important role in the induction of alpha-globin gene expression through disrupting the interaction of Bach1 and the NA site in HS-40 enhancer in erythroid cells.
    Biochemical and Biophysical Research Communications 12/2004; 324(1):77-85. · 2.41 Impact Factor
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    ABSTRACT: Bach1 is a transcriptional repressor of heme oxygenase-1 and beta-globin genes, both of which are known to be transcriptionally induced by heme. To test the hypothesis that heme regulates the activity of Bach1, we expressed wild type and mutated versions of Bach1 together with or without its heterodimer partner MafK in human 293T and GM02063 cells and examined their subcellular localization. Inhibition of heme synthesis enhanced the nuclear accumulation of Bach1, whereas treating cells with hemin resulted in nuclear exclusion of Bach1. While the cadmium-inducible nuclear export signal (NES) of Bach1 was dispensable for the heme response, a region containing two of the heme-binding motifs was found to be critical for the heme-induced nuclear exclusion. This region functioned as a heme-regulated NES dependent on the exporter Crm1. These results extend the regulatory roles for heme in protein sorting, and suggest that Bach1 transduces metabolic activity into gene expression.
    The EMBO Journal 08/2004; 23(13):2544-53. · 9.82 Impact Factor
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    ABSTRACT: Small Maf proteins serve as dual-function transcription factors through an exchange of their heterodimerization partners. For example, as heterodimers with hematopoietic cell-specific p45 NF-E2 or NF-E2-related factors (Nrf), they activate the beta-globin or antioxidative stress enzyme heme oxygenase 1 (HO-1) genes, respectively. In contrast, together with Bach1, they repress these same genes. However, the signals leading to this partner exchange are not known. Using chromatin immunoprecipitation assays in NIH 3T3 cells, we show that heme, an inducer of ho-1, promotes displacement of Bach1 from the MafK-occupied ho-1 enhancers, which is followed by Nrf2 binding to these elements. Whereas histone H3 at the ho-1 enhancers and promoter is hyperacetylated irrespective of gene activity, exposure of cells to heme results in de novo hyperacetylation and hypermethylation of histone H3 in the transcribed region. These data indicate that, under normal conditions, the chromatin structure of ho-1 is in a preactivation state, but transcription is repressed by Bach1. Heme induces switching of Maf dimers, resulting in ho-1 expression. Heme also promotes displacement of Bach1 from the beta-globin locus control region without affecting MafK binding in murine erythroleukemia cells. Thus, heme functions as a signaling molecule for gene expression in higher eukaryotes.
    Proceedings of the National Academy of Sciences 03/2004; 101(6):1461-6. · 9.81 Impact Factor

Publication Stats

839 Citations
113.05 Total Impact Points

Institutions

  • 2007–2014
    • Hiroshima University
      • • Department of Cellular Biology
      • • Department of Surgical Oncology
      • • Department of Neurosurgery
      Hirosima, Hiroshima, Japan
  • 2006
    • Tohoku University
      • Department of Biochemistry
      Sendai-shi, Miyagi-ken, Japan