Stringent regulation of DNA repair during human hematopoietic differentiation: A gene expression and functional analysis
Stringent regulation of DNA repair during human hematopoietic differentiation: A gene expression and functional analysis
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DOI：
10.1634/stemcells.2005-0227
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发表时间：
2006-03-01
期刊：
影响因子：
5.2
通讯作者：
Thomale, Juergen
中科院分区：
文献类型：
--
作者：
Bracker, Tomke U.;Giebel, Bernd;Thomale, Juergen
对于淋巴造血系统，DNA修复功能的成熟依赖性改变已被证明。因为很少有信息是关于这些变化背后的调控机制，我们相关的DNA损伤反应基因的表达和功能修复能力的细胞在不同阶段的人造血分化。比较从脐带血中分离的成熟细胞（CD 34（-））、祖细胞（CD 34（+）38（+））和干细胞（CD 34（+）38（-））的分数，我们观察到：1）DNA损伤的细胞加工和相关基因的表达谱两者中严格调节的分化依赖性转变，和2）在转录和功能水平上，DNA修复具有相当大的个体间变异性。相应的修复表型被认为是组成性调节，而不是由适应性反应急性DNA损伤为主。在血细胞发育过程中，与同一个体的祖细胞相比，干细胞或成熟细胞中DNA加合物的去除、修复间隙的重新密封、对DNA反应性药物的抗性明显增加。另一方面，绝大多数差异表达的修复基因在祖细胞组分中一致上调。研究发现，RAD 23或ATM等少数基因的修复功能与转录水平呈正相关，这些基因可能是通过特定途径进行DNA损伤处理的关键调控因子。这些数据表明，生物体的目的可能是通过广泛的DNA修复来保护少量有价值的缓慢分裂的干细胞，而快速增殖的祖细胞一旦受损，就会被细胞凋亡所消除。
For the lymphohematopoietic system, maturation-dependent alterations in DNA repair function have been demonstrated. Because little information is available on the regulatory mechanisms underlying these changes, we have correlated the expression of DNA damage response genes and the functional repair capacity of cells at distinct stages of human hematopoietic differentiation. Comparing fractions of mature (CD34(-)), progenitor (CD34(+)38(+)), and stem cells (CD34(+)38(-)) isolated from umbilical cord blood, we observed: 1) stringently regulated differentiation-dependent shifts in both the cellular processing of DNA lesions and the expression profiles of related genes and 2) considerable interindividual variability of DNA repair at transcriptional and functional levels. The respective repair phenotype was found to be constitutively regulated and not dominated by adaptive response to acute DNA damage. During blood cell development, the removal of DNA adducts, the resealing of repair gaps, the resistance to DNA-reactive drugs clearly increased in stem or mature compared with progenitor cells of the same individual. On the other hand, the vast majority of differentially expressed repair genes was consistently upregulated in the progenitor fraction. A positive correlation of repair function and transcript levels was found for a small number of genes such as RAD23 or ATM, which may serve as key regulators for DNA damage processing via specific pathways. These data indicate that the organism might aim to protect the small number of valuable slow dividing stem cells by extensive DNA repair, whereas fast-proliferating progenitor cells, once damaged, are rather eliminated by apoptosis.