Identification of strong DNA binding motifs for bleomycin
Identification of strong DNA binding motifs for bleomycin
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DOI：
10.1021/ja802905g
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发表时间：
2008-07-30
影响因子：
15
通讯作者：
Hecht, Sidney M.
中科院分区：
文献类型：
--
作者：
Akiyama, Yoshitsugu;Ma, Qian;Hecht, Sidney M.
博来霉素（BLM）是临床上常用的抗肿瘤抗生素。它们的作用机制被认为涉及DNA的氧化裂解，也可能涉及RNA降解。DNA降解已被广泛研究，并显示涉及活化的金属球霉素与DNA的结合，随后在DNA降解的限速步骤中从脱氧核糖中提取C4 '-H。有趣的是，虽然DNA和RNA的降解活化铁中心点BLM已被广泛研究，少得多的是已知的BLM的实际结合的选择性，即，强制性的步骤之前，裂解。因此，尚不清楚切割特异性是否由结合事件定义或切割是否发生在优选结合位点的子集。除了少数例外，NMR结合研究采用了金属BLM，如Co中心点BLM和Zn中心点BLM，其治疗相关性是不确定的。一个单一的生物化学研究，比较DNA结合和切割直接也采用Co中心点BLM。合乎逻辑的是，预期DNA切割的优选位点将发生在作为优选DNA结合位点（的子集）的位点处，但目前没有与该问题相关的可用数据。在这里，我们描述了一种新的策略，以确定DNA基序结合BLM强烈的发展和实施。
The bleomycins (BLMs) are clinically used antitumor antibiotics. Their mechanism of action is believed to involve oxidative cleavage of DNA and possibly also RNA degradation. DNA degradation has been studied extensively and shown to involve binding of an activated metallobleomycin to DNA, followed by abstraction of C4'-H from deoxyribose in the rate-limiting step for DNA degradation. It is interesting that while DNA and RNA degradation by activated Fe center dot BLM has been studied extensively, much less is known about the actual binding selectivity of BLM, that is, the obligatory step that precedes cleavage. Thus it is unclear whether cleavage specificity is defined by the binding event or whether cleavage occurs at a subset of preferred binding sites. With only a few exceptions, NMR binding studies have employed metalloBLMs such as Co center dot BLM and Zn center dot BLM whose therapeutic relevance is uncertain. A single biochemical study that compared DNA binding and cleavage directly also employed Co center dot BLM. It is logical to anticipate that preferred sites of DNA cleavage will occur at sites that are (a subset of) preferred DNA binding sites, but there are currently no data available relevant to this issue. Herein, we describe the development and implementation of a novel strategy to identify DNA motifs that bind BLM strongly.