Designer enediynes generate DNA breaks, interstrand cross-links, or both, with concomitant changes in the regulation of DNA damage responses
Designer enediynes generate DNA breaks, interstrand cross-links, or both, with concomitant changes in the regulation of DNA damage responses
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DOI：
10.1073/pnas.0708274104
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发表时间：
2007-11-06
影响因子：
11.1
通讯作者：
Beerman, Terry A.
中科院分区：
文献类型：
--
作者：
Kennedy, Daniel R.;Ju, Jianhua;Beerman, Terry A.
拟放射抗癌烯二炔 C-1027 诱导共济失调毛细血管扩张突变 (ATM) 以及 ATM 和 Rad3 相关 (ATR) 独立损伤反应的能力在于其在细胞 DNA 中同时产生大量双链断裂 (DSB) 和链间交联 (ICL) 的独特能力。此外，发色团苯并恶唑啉酯部分的单一取代将 DNA 损伤主要转移到 ICL 和 ATR 依赖性损伤反应，而不是 ATM 依赖性损伤反应。相比之下，发色团的β-氨基酸成分的单一取代将DNA损伤主要转移到DSB，这与其诱导由电离辐射和其他放射模拟物产生的传统ATM依赖性损伤反应一致。因此，磷脂酰肌醇 3 激酶样蛋白激酶对 DNA 损伤反应的调节是由 DSB 和 ICL 的相对比例决定的。
The ability of the radiomimetic anticancer enediyne C-1027 to induce ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR)-independent damage responses was discovered to reside in its unique ability to concurrently generate robust amounts of double-strand breaks (DSBs) and interstrand cross-links (ICLs) in cellular DNA. Furthermore, a single substitution to the chromophore's benzoxazolinate moiety shifted DNA damage to primarily ICLs and an ATR- but not ATM-dependent damage response. In contrast, single substitutions of the chromophore's p-amino acid component shifted DNA damage to primarily DSBs, consistent with its induction of conventional ATM-dependent damage responses of the type generated by ionizing radiation and other radiomimetics. Thus, phosphatidylinositol 3-kinase-like protein kinase regulation of DNA damage responses is dictated by the relative proportions of DSBs and ICLs.