DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP
DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP
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DNA 损伤反应可减少由膳食致癌物 PhIP 引起的有害复制应激和染色体不稳定
DOI：
10.1093/nar/gkw791
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发表时间：
2016
影响因子：
14.9
通讯作者：
Fahrer J
中科院分区：
文献类型：
--
作者：
Mimmler M;Peter S;Kraus A;Stroh S;Nikolova T;Seiwert N;Hasselwander S;Neitzel C;Haub J;Monien B;Nicken P;Steinberg P;Shay J;Kaina B;Fahrer J
PhIP是一种含量丰富的杂环芳香胺（HCA），是重要的膳食致癌物。在代谢活化后，PhIP在鸟嘌呤的C8位引起大体积DNA损伤。尽管C8-PhIP-dG加合物具有致突变性，但其对DNA复制机制的干扰和引发的DNA损伤反应（DDR）尚未研究。在此，我们分析了PhIP引发的复制应激，并阐明了顶端DDR激酶ATR，ATM和DNA-PKC在细胞防御反应中的作用。首先，我们证明了PhIP诱导C8-PhIP-dG加合物和DNA链断裂。这刺激了ATR-CHK 1信号传导、组蛋白2AX的磷酸化和RPA灶的形成。在增殖细胞中，PhIP处理增加了停滞的复制叉的频率并降低了叉的速度。在PhIP诱导的DNA损伤的存在下抑制ATR强烈促进DNA双链断裂的形成、ATM-CHK 2通路的激活和RPA的过度磷酸化。ATR信号传导的消除增强了细胞死亡反应，并增强了PhIP处理后的染色体畸变，而ATM和DNA-PK抑制只有边际效应。这些结果强烈支持ATR在防御PhIP和相关HCAs诱导的癌症形成中起关键作用的观点。
PhIP is an abundant heterocyclic aromatic amine (HCA) and important dietary carcinogen. Following metabolic activation, PhIP causes bulky DNA lesions at the C8-position of guanine. Although C8-PhIP-dG adducts are mutagenic, their interference with the DNA replication machinery and the elicited DNA damage response (DDR) have not yet been studied. Here, we analyzed PhIP-triggered replicative stress and elucidated the role of the apical DDR kinases ATR, ATM and DNA-PKcsin the cellular defense response. First, we demonstrate that PhIP induced C8-PhIP-dG adducts and DNA strand breaks. This stimulated ATR-CHK1 signaling, phosphorylation of histone 2AX and the formation of RPA foci. In proliferating cells, PhIP treatment increased the frequency of stalled replication forks and reduced fork speed. Inhibition of ATR in the presence of PhIP-induced DNA damage strongly promoted the formation of DNA double-strand breaks, activation of the ATM-CHK2 pathway and hyperphosphorylation of RPA. The abrogation of ATR signaling potentiated the cell death response and enhanced chromosomal aberrations after PhIP treatment, while ATM and DNA-PK inhibition had only marginal effects. These results strongly support the notion that ATR plays a key role in the defense against cancer formation induced by PhIP and related HCAs.
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影响因子：
4.1
作者：
LIN, DX;KADERLIK, KR;KADLUBAR, FF
通讯作者：
KADLUBAR, FF
正常和修复缺陷的人淋巴母细胞系中紫外线照射和芳香胺诱导的 DNA 损伤的修复。
影响因子：
4.7
作者：
T. Stevnsner;H. Frandsen;H. Autrup
通讯作者：
H. Autrup
影响因子：
11.4
作者：
Fang, Y;Tsao, CC;Wang, XF
通讯作者：
Wang, XF
影响因子：
3.8
作者：
Fahrer, Joerg;Huelsenbeck, Johannes;Fritz, Gerhard
通讯作者：
Fritz, Gerhard
影响因子：
4.1
作者：
Nauwelaers G;Bessette EE;Gu D;Tang Y;Rageul J;Fessard V;Yuan JM;Yu MC;Langouët S;Turesky RJ
通讯作者：
Turesky RJ