Wu Bin, Davey Curt A
Division of Structural and Computational Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Chem Biol. 2008 Oct 20;15(10):1023-8. doi: 10.1016/j.chembiol.2008.08.010.
Nucleosome positioning and reorganization regulate DNA site exposure in chromatin. Platinum anticancer agents form DNA adducts that disrupt nuclear activities, triggering apoptosis. Mechanistic insight would aid in the development of improved therapies to circumvent drug toxicity and resistance. We show that platinum adducts formed by reaction of cisplatin or oxaliplatin with the nucleosome core inhibit histone octamer-DNA sliding but do not cause significant alteration of positioning. Thus, adduct formation reinforces positional preferences intrinsic to the DNA sequence, which indicates that modulation of platinum drug site selectivity by histone octamer association may relate to nucleosome-specific properties of DNA. This sheds light on platinum drug-mediated inhibition of chromatin remodeling in vivo and suggests that adducts can shield their own repair and interfere with genomic activities by directly altering nucleosome dynamics.
核小体定位与重组调控染色质中DNA位点的暴露。铂类抗癌药物形成DNA加合物，破坏核活动，引发细胞凋亡。深入了解其作用机制将有助于开发改进疗法，以规避药物毒性和耐药性。我们发现，顺铂或奥沙利铂与核小体核心反应形成的铂加合物抑制组蛋白八聚体-DNA滑动，但不会导致定位发生显著改变。因此，加合物的形成强化了DNA序列固有的定位偏好，这表明组蛋白八聚体结合对铂类药物位点选择性的调节可能与DNA的核小体特异性特性有关。这揭示了铂类药物在体内介导的染色质重塑抑制作用，并表明加合物可以保护自身修复，通过直接改变核小体动力学干扰基因组活动。
