Effects of photochemically activated alkylating agents of the FR900482 family on chromatin.
Bioreductive alkylating agents are an important class of clinical antitumor antibiotics that crosslink and monoalkylate DNA. Here, we use a synthetic, photochemically activated derivative of FR400482 to investigate the molecular mechanism of this class of drugs in a biologically relevant context. We find that the organization of DNA into nucleosomes effectively protects it against drug-mediated crosslinking, while permitting monoalkylation. This modification has the potential to lead to the formation of covalent crosslinks between chromatin and nuclear proteins. Using in vitro approaches, we found that interstrand crosslinking of free DNA results in a significant decrease in basal and activated transcription. Finally, crosslinked plasmid DNA is inefficiently assembled into chromatin. Our studies suggest pathways for the clinical effectiveness of this class of reagents.
Subramanian
Vidya
V
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USA.
Ducept
Pascal
P
Williams
Robert M
RM
Luger
Karolin
K
D000478:Alkylation; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000494:pharmacology*; D002843:Chromatin / Q000737:chemistry* / Q000187:drug effects*; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004276:DNA, Satellite / Q000737:chemistry / Q000235:genetics; D004587:Electrophoresis, Agar Gel; D006657:Histones / Q000737:chemistry; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism; D010078:Oxazines / Q000737:chemistry; D010777:Photochemistry; D014158:Transcription, Genetic / Q000187:drug effects
D018906:Antineoplastic Agents, Alkylating; D002843:Chromatin; D003432:Cross-Linking Reagents; D004276:DNA, Satellite; D006657:Histones; D009707:Nucleosomes; D010078:Oxazines; C053335:FR 900482; D004247:DNA