Specific gain- and loss-of-function phenotypes induced by satellite-specific DNA-binding drugs fed to Drosophila melanogaster

• Published in: Molecular cell Vol. 6; no. 5; pp. 1013 - 1024
• Main Authors: Janssen, S, Cuvier, O, Müller, M, Laemmli, U K
• Format: Journal Article
• Language: English
• Published: United States 01.11.2000
• Subjects: Alleles; Animals; AT Rich Sequence - genetics; Base Sequence; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Chromatin - chemistry; Chromatin - drug effects; Chromatin - genetics; Chromatin - metabolism; DNA, Satellite - genetics; DNA, Satellite - metabolism; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - pharmacology; Drosophila melanogaster; Drosophila melanogaster - cytology; Drosophila melanogaster - drug effects; Drosophila melanogaster - genetics; Drosophila melanogaster - growth & development; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Eye - drug effects; Eye - growth & development; Eye - metabolism; Gene Expression Regulation, Developmental - drug effects; Genes, Dominant - genetics; Genes, Homeobox - genetics; Genes, Insect - genetics; Homeodomain Proteins - metabolism; Mutation - genetics; Nylons - metabolism; Nylons - pharmacology; Phenotype; polyamides; Substrate Specificity; Transcription Factors - metabolism
• ISSN: 1097-2765
• DOI: 10.1016/s1097-2765(00)00100-3

DNA-binding pyrrole-imidazole compounds were synthesized that target different Drosophila melanogaster satellites. Compound P31 specifically binds the GAGAA satellite V, and P9 targets the AT-rich satellites I and III. Remarkably, these drugs, when fed to developing Drosophila flies, caused gain- or loss-of-function phenotypes. While polyamide P9 (not P31) suppressed PEV of white-mottled flies (increased gene expression), P31 (not P9) mediated three well-defined, homeotic transformations (loss-of-function) exclusively in brown-dominant flies. Both phenomena are explained at the molecular level by chromatin opening (increased accessibility) of the targeted DNA satellites. Chromatin opening of satellite III by P9 is proposed to suppress PEV of white-mottled flies, whereas chromatin opening of satellite V by P31 is proposed to create an inopportune "sink" for the GAGA factor (GAF).