Echinomycin inhibits chromosomal DNA replication and embryonic development in vertebrates.
Echinomycin, a member of the quinoxaline family of antibiotics, is known to be a strong inhibitor of RNA synthesis which has been attributed to its ability to bind to double-helical DNA. Here we study the effect of echinomycin upon DNA replication using egg extracts and embryos from Xenopus laevis as well as cultured human cells. Evidence is presented that echinomycin interferes with chromatin decondensation, nuclear assembly and DNA replication. In the absence of transcription and translation, the drug specifically blocks DNA replication in both Xenopus sperm chromatin and HeLa cell nuclei in vitro. By contrast, replication of single-stranded DNA is not inhibited indicating that echinomycin acts by interacting with the DNA and not the replication elongation proteins of chromatin. The addition of the antibiotic to HeLa cells and X.laevis embryos results in anaphase bridges and cell death. Importantly, in X.laevis embryos injected with echinomycin at the two-cell stage the drug specifically inhibits the cell cycle prior to the onset of transcription, suggesting that quinoxaline antibiotics could exert anti- proliferative effects by inhibition of chromosomal DNA replication.
May
Laurence G
LG
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
Madine
Mark A
MA
Waring
Michael J
MJ
D000705:Anaphase / Q000187:drug effects; D000818:Animals; D017104:Bacteriophage M13 / Q000235:genetics; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002457:Cell Extracts; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D002875:Chromosomes / Q000187:drug effects* / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects*; D004448:Echinomycin / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013094:Spermatozoa / Q000166:cytology / Q000187:drug effects; D013950:Thymus Gland; D014158:Transcription, Genetic / Q000187:drug effects; D014982:Xenopus laevis / Q000196:embryology* / Q000235:genetics*
D002457:Cell Extracts; D002843:Chromatin; D004448:Echinomycin; D004247:DNA