國家衛生研究院 NHRI:Item 3990099045/2892
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    題名: A novel topoisomerase II poison GL331 preferentially induces DNA cleavage at (C/G)T sites and can cause telomere DNA damage
    作者: Lee, CC;Huang, TS
    貢獻者: National Institute of Cancer Research
    摘要: Purpose Topoisomerase II (Topo II) preferentially cuts DNA at alternating purine-pyrimidine repeats. Different Topo II poisons may affect Topo II to produce distinct drug-specific DNA cleavage patterns. GL331 is a new podophyllotoxin derivative exhibiting potent Topo II-poisoning activity. Therefore, the sequence selectivity of GL331-induced DNA cleavage was determined. Methods, Human gastric adenocarcinoma SC-Mi cells were treated with GL331, and the resultant DNA fragments were isolated by SDS-K+; precipitation. These DNA fragments were further cloned and sequenced to exhibit GL331-induced DNA cleavage sites. In addition, the telomere damage was detected by Southern blot analyses using a (TTAGGG)(4) probe. GL331's effect on telomerase was examined using the TRAP assay. Results. The selective sequences of GL331-induced DNA cleavage were analyzed. The first nucleotide 3 ' -terminal to the cleavage sites was preferentially C or Ci and followed by the second nucleotide T. More than 50% of GL331-induced DNA cleavage fragments exhibited AT-rich sequences in the first 20 nucleotides. In addition, the telomeric damage was observed both from GL331-treated SC-MI cells and in vitro incubation of genomic DNA with GL331 and purified human Topo II. Although GL331 treatment reduced cellular telomerase activity lit vitro reaction data suggested that GL331 was not a telomerase inhibitor. Conclusions. GL331 preferentially induced Topo II-mediated DNA cleavage at (C/G)T sites. Because the telomeric repeat sequence contains GL331's GT preference site, the telomere was identified as one of the targets of GL331-induced DNA damage.
    關鍵詞: Chemistry, Multidisciplinary;Pharmacology & Pharmacy
    日期: 2001-06
    關聯: Pharmaceutical Research. 2001 Jun;18(6):846-851.
    Link to: http://dx.doi.org/10.1023/A:1011048831698
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0724-8741&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000169834700018
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0034858972
    顯示於類別:[黃智興] 期刊論文

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