Rabbani Azra, Finn Ron M, Thambirajah Anita A, Ausió Juan
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
Biochemistry. 2004 Dec 28;43(51):16497-504. doi: 10.1021/bi048524p.
Daunomycin is an anticancer drug that is well-known to interact with DNA in chromatin. Using a compositionally defined chicken erythrocyte chromatin fraction, we have obtained conclusive evidence that the drug is also able to interact with chromatin-bound linker histones without any noticeable binding to core histones. The drug can interact in an equal fashion with both histone H1 and H5 and to a greater extent with core histones H3/H4 and H2A/H2B as free proteins in solution. Thus, the binding of daunomycin to linker histones in the chromatin fiber is most likely due to the well-known higher accessibility of these histones to the surrounding environment of the fiber. Binding of daunomycin to linker histones appears to primarily involve the trypsin-resistant (winged-helix) domain of these proteins. The studies described here reveal the occurrence of a previously undisclosed mechanism for the antitumor activity of anthracycline drugs at the chromatin level.
柔红霉素是一种众所周知的能与染色质中的DNA相互作用的抗癌药物。利用成分明确的鸡红细胞染色质组分，我们获得了确凿证据，表明该药物还能够与染色质结合的连接组蛋白相互作用，而对核心组蛋白没有任何明显的结合。该药物能以相同方式与组蛋白H1和H5相互作用，并且在溶液中作为游离蛋白质时，与核心组蛋白H3/H4和H2A/H2B的相互作用程度更大。因此，柔红霉素与染色质纤维中连接组蛋白的结合很可能是由于这些组蛋白对纤维周围环境具有更高的可及性，这是众所周知的。柔红霉素与连接组蛋白的结合似乎主要涉及这些蛋白质的抗胰蛋白酶（翼状螺旋）结构域。此处描述的研究揭示了蒽环类药物在染色质水平上抗肿瘤活性存在一种以前未被发现的机制。
