Thrombopoietin-lncreased DNA-PK-Dependent DNA Repair Limits Hematopoietic Stem and Progenitor Cell Mutagenesis in Response to DNA Damage
Thrombopoietin-lncreased DNA-PK-Dependent DNA Repair Limits Hematopoietic Stem and Progenitor Cell Mutagenesis in Response to DNA Damage
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DOI：
10.1016/j.stem.2012.10.012
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发表时间：
2013-01-03
期刊：
影响因子：
23.9
通讯作者：
Porteu, Francoise
中科院分区：
文献类型：
--
作者：
de Laval, Berengere;Pawlikowska, Patrycja;Porteu, Francoise
DNA双链断裂（DSB）是造血干细胞（HSC）的严重威胁。细胞因子和环境信号如何整合DNA损伤反应并促进HSC内在DNA修复过程仍然未知。血小板生成素（TPO）及其受体Mpl是支持HSC自我更新和扩增的关键因子。在这里，我们发现了一个未知的功能TPO-Mpl在调节DNA损伤反应。我们发现，DNA修复后γ-照射（γ-IR）或拓扑异构酶-II抑制剂的作用是有缺陷的Mpl（-/-）和野生型小鼠或人类造血干细胞和祖细胞在TPO的情况下处理。TPO通过增加DNA-PK依赖的非同源末端连接效率在体外和体内刺激DNA修复。这确保了HSC染色体的完整性，并限制了它们对IR的长期损伤。这表明，生态位因子可以调节HSC DSB修复机制，并为TPO激动剂的给药开辟了新的途径，以最大限度地减少放疗诱导的HSC损伤和诱变。
DNA double-strand breaks (DSBs) represent a serious threat for hematopoietic stem cells (HSCs). How cytokines and environmental signals integrate the DNA damage response and contribute to HSC-intrinsic DNA repair processes remains unknown. Thrombopoietin (TPO) and its receptor, Mpl, are critical factors supporting HSC self-renewal and expansion. Here, we uncover an unknown function for TPO-Mpl in the regulation of DNA damage response. We show that DNA repair following gamma-irradiation (gamma-IR) or the action of topoisomerase-II inhibitors is defective in Mpl(-/-) and in wild-type mouse or human hematopoietic stem and progenitor cells treated in the absence of TPO. TPO stimulates DNA repair in vitro and in vivo by increasing DNA-PK-dependent nonhomologous end-joining efficiency. This ensures HSC chromosomal integrity and limits their long-term injury in response to IR. This shows that niche factors can modulate the HSC DSB repair machinery and opens new avenues for administration of TPO agonists for minimizing radiotherapy-induced HSC injury and mutagenesis.