FR900482家族光化学活化烷基化剂对染色质的影响。
Effects of photochemically activated alkylating agents of the FR900482 family on chromatin.
作者信息
Subramanian Vidya, Ducept Pascal, Williams Robert M, Luger Karolin
机构信息
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523, USA.
出版信息
Chem Biol. 2007 May;14(5):553-63. doi: 10.1016/j.chembiol.2007.04.004.
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.
生物还原烷基化剂是一类重要的临床抗肿瘤抗生素，可使DNA交联并单烷基化。在此，我们使用FR400482的一种合成的、光化学活化衍生物，在生物学相关背景下研究这类药物的分子机制。我们发现，DNA组装成核小体可有效保护其免受药物介导的交联，同时允许单烷基化。这种修饰有可能导致染色质与核蛋白之间形成共价交联。使用体外方法，我们发现游离DNA的链间交联会导致基础转录和活化转录显著减少。最后，交联的质粒DNA组装成染色质的效率低下。我们的研究提出了这类试剂临床有效性的途径。
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