title: Synergistic induction of the senescence-associated genes by 5-bromodeoxyuridine and AT-binding ligands in HeLa cells.
abstract: 5-Bromodeoxyuridine induces a senescence-like phenomenon in mammalian cells. This effect was dramatically potentiated by AT-binding ligands such as distamycin A, netropsin, and Hoechst 33258. The genes most remarkably affected by these ligands include the widely used senescence-associated genes and were located on or nearby Giemsa-dark bands of human chromosomes. We hypothesize that AT-rich scaffold/nuclear matrix attachment region sequences are involved in this phenomenon. In fact, upon substitution of thymine with 5-bromouracil, a rat S/MAR sequence reduced its degree of bending and became insensitive to cancellation of the bending by distamycin A. The S/MAR sequence containing 5-bromouracil also bound more tightly to nuclear scaffold proteins in vitro and this binding was not inhibited by distamycin A. Under the same conditions, the S/MAR sequence containing thymine easily dissociated from the nuclear scaffold proteins. Taken together, the synergistic induction of the genes may be explained not only by opening of condensed chromatin by distamycin A but also by increase in the binding of 5-bromouracil-containing S/MAR sequences to the nuclear scaffolds.
authors.affiliation: Kihara Institute for Biological Research and Graduate School of Integrated Science, Yokohama City University, Maioka-cho 641-12, Yokohama 244-0813, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Eriko
authors.initials: E
authors.lastname: Michishita
authors.forename: Hideki
authors.initials: H
authors.lastname: Ogino
authors.forename: Michihiko
authors.initials: M
authors.lastname: Fujii
authors.forename: Dai
authors.initials: D
authors.lastname: Ayusawa
mesh_terms: D020856:AT Rich Sequence / Q000187:drug effects / Q000235:genetics*; D000998:Antiviral Agents / Q000494:pharmacology; D006690:Bisbenzimidazole / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D001976:Bromouracil / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D002874:Chromosome Mapping; D004247:DNA / Q000187:drug effects / Q000235:genetics; D004214:Distamycins / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005057:Eukaryotic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005796:Genes / Q000187:drug effects / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D009429:Netropsin / Q000494:pharmacology; D015530:Nuclear Matrix / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D004214:Distamycins; D005456:Fluorescent Dyes; D009687:Nuclear Proteins; D012333:RNA, Messenger; D001976:Bromouracil; D009429:Netropsin; C030000:stallimycin; D004247:DNA; D001973:Bromodeoxyuridine; D006690:Bisbenzimidazole