Maintenance of genomic integrity in hematopoietic stem cells
Maintenance of genomic integrity in hematopoietic stem cells
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DOI：
10.1007/s12185-011-0793-z
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发表时间：
2011-04-01
影响因子：
2.1
通讯作者：
Hirao, Atsushi
中科院分区：
文献类型：
--
作者：
Naka, Kazuhito;Hirao, Atsushi
造血干细胞(HSCs)通过自我更新和分化为成熟的血细胞，在哺乳动物的整个生命周期中维持造血稳态。在骨髓穴内，造血干细胞处于静止状态，并保持在细胞周期的未分裂的G0期。最近的研究表明，保持基因组的完整性是维持造血干细胞自我更新能力的关键。在这篇综述中，我们重点阐述了活性氧(ROS)和DNA损伤反应(DDR)在维持基因组完整性和HSC功能方面的作用。一些研究表明，由于ATM、PI3K-Akt或MDM2-P53通路的中断而导致的不适当的ROS水平会损害体内HSC的功能。干细胞使用特定的DDR机制的耐人寻味的证据也在积累。尽管小鼠HSCs在体内对轻微的DNA损伤比祖细胞更具抵抗力，但幸存的HSCs经常获得可能导致白血病发生的遗传异常。事实上，非分裂的HSCs使用容易出错的非同源末端连接DNA修复途径来修复DNA断裂，而祖细胞经历凋亡；增殖的HSCs使用高保真的同源重组机制。对维持基因组完整性的HSC特异性机制的剖析可能会为HSC和白血病干细胞的生物学提供有价值的见解。
Hematopoietic stem cells (HSCs) maintain hematopoietic homeostasis throughout a mammal's lifespan through self-renewal and differentiation into mature blood cells. Within a bone marrow niche, HSCs adopt a quiescent state and remain in the non-dividing, G0 phase of the cell cycle. It was recently shown that maintenance of genomic integrity is crucial for the preservation of self-renewal capacity of HSCs. In this review, we focus on progress in elucidating the roles of reactive oxygen species (ROS) and DNA damage responses (DDR) in maintaining genomic integrity, and thus HSC function. Several studies have demonstrated that inappropriate ROS levels arising from disruption of the Atm, PI3K-Akt, or Mdm2-p53 pathways impair HSC function in vivo. Intriguing evidence that stem cells use specific DDR mechanisms is also accumulating. Although murine HSCs are more resistant than progenitor cells to mild DNA damage in vivo, the surviving HSCs frequently acquire genetic aberrations that can lead to leukemogenesis. Indeed, non-dividing HSCs employ the error-prone non-homologous end-joining pathway of DNA repair to fix DNA breaks, whereas progenitors undergo apoptosis; proliferating HSCs employ the high-fidelity homologous recombination mechanism. Dissection of HSC-specific mechanisms for the maintenance of genomic integrity may provide valuable insights into the biology of both HSCs and leukemia stem cells.