CHK1 and RAD51 activation after DNA damage is regulated via urokinase receptor/TLR4 signaling.
CHK1 and RAD51 activation after DNA damage is regulated via urokinase receptor/TLR4 signaling.
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DOI：
10.1038/cddis.2016.291
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发表时间：
2016-09-29
影响因子：
9
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中科院分区：
文献类型：
--
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DNA损伤和修复信号的机制尚不完全清楚，这些机制阻碍了癌症治疗的效率。尿激酶型纤溶酶原激活剂受体(PLAUR)在大多数实体癌中高表达，是预后不良的标志。我们发现PLAUR积极促进癌细胞的DNA修复。相反，PLAUR表达下调会导致DNA修复延迟。我们发现PLAUR在以下过程中是必不可少的：激活检查点激酶1(CHK1)；以TP53依赖的方式维持DNA损伤后的细胞周期停滞；RAD51重组酶的表达、核输入和募集到DNA损伤灶中，RAD51重组酶是参与同源重组修复途径的主要蛋白质。潜在的机制是PLAUR/TLR4受体复合体的自身/旁分泌信号导致CHK1的激活和DNA修复。该信号是由DNA损伤细胞释放的危险分子诱导的，并至少部分介导了DNA损伤反应的激活。本研究描述了一种由膜受体PLAUR/TLR4的自身/旁分泌信号启动的DNA修复激活的新机制。这增加了对PLAUR在癌症中的作用的理解，并为在TP53阳性的癌症中靶向PLAUR/TLR4相互作用提供了理论基础。
Mechanisms of DNA damage and repair signaling are not completely understood that hinder the efficiency of cancer therapy. Urokinase-type plasminogen activator receptor (PLAUR) is highly expressed in most solid cancers and serves as a marker of poor prognosis. We show that PLAUR actively promotes DNA repair in cancer cells. On the contrary, downregulation of PLAUR expression results in delayed DNA repair. We found PLAUR to be essential for activation of Checkpoint kinase 1 (CHK1); maintenance of cell cycle arrest after DNA damage in a TP53-dependent manner; expression, nuclear import and recruitment to DNA-damage foci of RAD51 recombinase, the principal protein involved in the homologous recombination repair pathway. Underlying mechanism implies auto-/paracrine signaling of PLAUR/TLR4 receptor complex leading to activation of CHK1 and DNA repair. The signaling is induced by a danger molecule released by DNA-damaged cells and mediates, at least partially, activation of DNA-damage response. This study describes a new mechanism of DNA repair activation initiated by auto-/paracrine signaling of membrane receptors PLAUR/TLR4. It adds to the understanding of role of PLAUR in cancer and provides a rationale for therapeutic targeting of PLAUR/TLR4 interaction in TP53-positive cancers.
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