Vanillins - a novel family of DNA-PK inhibitors
Vanillins - a novel family of DNA-PK inhibitors
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DOI：
10.1093/nar/gkg753
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发表时间：
2003-10-01
影响因子：
14.9
通讯作者：
Karran, P
中科院分区：
文献类型：
--
作者：
Durant, S;Karran, P
非同源DNA末端连接（NHEJ）是人类细胞中双链断裂（DSB）修复的主要途径。在这里，我们表明，香草醛（3-甲氧基-4-羟基苯甲醛）-一种天然存在的食品成分和公认的抗突变剂，抗细胞凋亡剂和抗癌剂-是NHEJ的抑制剂。香草醛通过直接抑制DNA-PK（一种关键的NHEJ组分）的活性来阻断人类细胞提取物的DNA末端连接。抑制是选择性的，香草醛对NHEJ过程的其他步骤，对不相关的蛋白激酶或细胞提取物对DNA错配修复没有可检测的影响。亚毒性浓度的香草醛不影响ATM/ATR依赖的磷酸化Chk 2或S-期检查点反应后电离辐射。它们显著增强顺铂的细胞毒性，但不影响对UVC的敏感性。结构相关化合物的有限筛选鉴定了两种取代的香草醛衍生物，其作为DNA-PK抑制剂的效力比香草醛高100倍和50倍。这些化合物也使细胞对顺铂敏感。NHEJ的抑制与香草醛的抗突变和其他生物学特性一致，可能改变NHEJ和同源重组的DSB修复之间的平衡。
Non-homologous DNA end-joining (NHEJ) is a major pathway of double strand break (DSB) repair in human cells. Here we show that vanillin (3-methoxy-4-hydroxybenzaldehyde)-a naturally occurring food component and an acknowledged antimutagen, anticlastogen and anticarcinogen-is an inhibitor of NHEJ. Vanillin blocked DNA end-joining by human cell extracts by directly inhibiting the activity of DNA-PK, a crucial NHEJ component. Inhibition was selective and vanillin had no detectable effect on other steps of the NHEJ process, on an unrelated protein kinase or on DNA mismatch repair by cell extracts. Subtoxic concentrations of vanillin did not affect the ATM/ATR-dependent phosphorylation of Chk2 or the S-phase checkpoint response after ionising radiation. They significantly potentiated the cytotoxicity of cisplatin, but did not affect sensitivity to UVC. A limited screen of structurally related compounds identified two substituted vanillin derivatives that were 100- and 50-fold more potent than vanillin as DNA-PK inhibitors. These compounds also sensitised cells to cisplatin. The inhibition of NHEJ is consistent with the antimutagenic and other biological properties of vanillin, possibly altering the balance between DSB repair by NHEJ and homologous recombination.