Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1
Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1
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DOI：
10.1182/blood-2013-07-515874
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发表时间：
2014-01-23
期刊：
影响因子：
20.3
通讯作者：
Porteu, Francoise
中科院分区：
文献类型：
--
作者：
de Laval, Berengere;Pawlikowska, Patrycja;Porteu, Francoise
造血干细胞（HSC）功能的丧失和发生造血系统恶性肿瘤的风险增加是严重的，并涉及抗癌放疗和化疗的并发症。我们以前已经表明，血小板生成素（TPO），一个关键的HSC调节器，确保HSC染色体的完整性和功能，通过调节他们的DNA损伤反应，以响应γ-辐射。TPO通过增加DNA-蛋白激酶（DNA-PK）磷酸化和非同源末端连接（NHEJ）修复效率和保真度直接影响双链断裂（DSB）修复机制。这种效应不被其他HSC生长因子共享，表明TPO触发HSC中的特异性信号，促进DNA损伤后的DNA-PK活化。这些独特信号通路的发现将提供一种增强TPO对HSC的期望作用和提高抗癌DNA试剂的安全性的手段。我们在这里显示，TPO特异性触发Erk和核因子κ B（NF-κ B）途径在小鼠造血干细胞和祖细胞（HSPC）。这两种途径都是TPO介导的DSB修复增加所必需的。它们在DNA损伤时协同诱导和激活早期应激反应基因Iex-1（ier 3）。Iex-1与pERK和DNA-PK的催化亚基形成复合物，这对于促进小鼠和人HSPC中TPO增加的DNA-PK活化和NHEJ DSB修复是必要且足够的。
Loss of hematopoietic stem cell (HSC) function and increased risk of developing hematopoietic malignancies are severe and concerning complications of anticancer radiotherapy and chemotherapy. We have previously shown that thrombopoietin (TPO), a critical HSC regulator, ensures HSC chromosomal integrity and function in response to gamma-irradiation by regulating their DNA-damage response. TPO directly affects the double-strand break (DSB) repair machinery through increased DNA-protein kinase (DNA-PK) phosphorylation and nonhomologous end-joining (NHEJ) repair efficiency and fidelity. This effect is not shared by other HSC growth factors, suggesting that TPO triggers a specific signal in HSCs facilitating DNA-PK activation upon DNA damage. The discovery of these unique signaling pathways will provide a means of enhancing TPO-desirable effects on HSCs and improving the safety of anticancer DNA agents. We show here that TPO specifically triggers Erk and nuclear factor kappa B (NF-kappa B) pathways in mouse hematopoietic stem and progenitor cells (HSPCs). Both of these pathways are required for a TPO-mediated increase in DSB repair. They cooperate to induce and activate the early stress-response gene, Iex-1 (ier3), upon DNA damage. Iex-1 forms a complex with pERK and the catalytic subunit of DNA-PK, which is necessary and sufficient to promote TPO-increased DNA-PK activation and NHEJ DSB repair in both mouse and human HSPCs.