FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage
FOXO3 Transcription Factor Is Essential for Protecting Hematopoietic Stem and Progenitor Cells from Oxidative DNA Damage
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DOI：
10.1074/jbc.m116.769455
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发表时间：
2017-02-17
影响因子：
4.8
通讯作者：
Ghaffari, Saghi
中科院分区：
文献类型：
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作者：
Bigarella, Carolina L.;Li, Jianfeng;Ghaffari, Saghi
造血干细胞（HSC）中受损DNA的积累与染色体异常、基因组不稳定性和HSC老化有关，并可能随着年龄的增长而促进血液恶性肿瘤的发生。尽管如此，HSC DNA损伤反应中涉及的调控途径尚未完全阐明。DNA损伤的来源之一是由外源性和内源性损伤产生的活性氧（ROS）。平衡HSC中的ROS水平需要FOXO 3，FOXO 3是HSC老化中涉及的HSC维持的重要转录因子。升高的ROS水平导致缺陷的Foxo 3（-/-）HSC循环，以及许多其他缺陷。在这里，我们表明，FOXO 3的损失导致原始造血干细胞和祖细胞（HSPC）中DNA损伤的积累，特别是与氧化DNA损伤修复相关的基因表达减少。我们提供了进一步的证据表明Foxo 3（-/-）HSPC在DNA损伤修复中有缺陷。具体而言，我们表明，碱基切除修复途径，用于修复氧化DNA损伤的主要途径，是受损的Foxo 3（-/-）原始造血细胞。用N-乙酰半胱氨酸在体内治疗小鼠降低ROS水平，挽救HSC循环缺陷，并部分减轻HSPC DNA损伤。这些结果表明，Foxo 3（-/-）突变体HSPC中由于活性氧升高而产生的DNA损伤至少部分可逆。总的来说，我们的研究结果表明FOXO 3是HSC基因组稳定性和健康的保护者。
Accumulation of damaged DNA in hematopoietic stem cells (HSC) is associated with chromosomal abnormalities, genomic instability, and HSC aging and might promote hematological malignancies with age. Despite this, the regulatory pathways implicated in the HSC DNA damage response have not been fully elucidated. One of the sources of DNA damage is reactive oxygen species (ROS) generated by both exogenous and endogenous insults. Balancing ROS levels in HSC requires FOXO3, which is an essential transcription factor for HSC maintenance implicated in HSC aging. Elevated ROS levels result in defective Foxo3(-/-) HSC cycling, among many other deficiencies. Here, we show that loss of FOXO3 leads to the accumulation of DNA damage in primitive hematopoietic stem and progenitor cells (HSPC), associated specifically with reduced expression of genes implicated in the repair of oxidative DNA damage. We provide further evidence that Foxo3(-/-) HSPC are defective in DNAdamage repair. Specifically, we show that the base excision repair pathway, the main pathway utilized for the repair of oxidative DNA damage, is compromised in Foxo3(-/-) primitive hematopoietic cells. Treating mice in vivo withN-acetylcysteine reduces ROS levels, rescues HSC cycling defects, and partially mitigates HSPC DNA damage. These results indicate that DNA damage accrued as a result of elevated ROS in Foxo3(-/-) mutant HSPC is at least partially reversible. Collectively, our findings suggest that FOXO3 serves as a protector of HSC genomic stability and health.