X-rays induce distinct patterns of somatic mutation in fetal versus adult hematopoietic cells
X-rays induce distinct patterns of somatic mutation in fetal versus adult hematopoietic cells
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DOI：
10.1016/j.dnarep.2007.04.005
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发表时间：
2007-09-01
期刊：
影响因子：
3.8
通讯作者：
Schfieda, Jay A.
中科院分区：
文献类型：
--
作者：
Liang, Li;Deng, Li;Schfieda, Jay A.
有多种机制和途径使细胞在面对损害DNA的环境损伤时保护其基因组。然而，这些途径中的每一个在哺乳动物的特定发育阶段是否同样强大，以及它们是否也以组织特异性方式进行调节，目前尚不清楚。在这里，我们报告说，电离辐射（IR）产生不同类型的体细胞突变的胎儿细胞相比，成人细胞相同的血统。虽然1戈伊的X射线显着诱导成年小鼠的T细胞基因内点突变，没有观察到点突变的影响时，应用于胎儿。另一方面，胎儿暴露于IR导致T细胞中有丝分裂重组的显著升高，这在成人中未观察到。碱基切除修复（BER）的活性显着低于胎儿造血细胞比成人细胞，由于低水平的DNA聚合酶p，BER的限速酶。在胎儿造血细胞中，这种低BER活性，加上高增殖率，导致X射线诱导的DNA损伤，如碱基损伤，单链断裂和双链断裂，通过同源重组修复，我们观察到有丝分裂重组。较高的BER活性和相对较低的细胞增殖速率可能有助于在成人中显著诱导DNA点突变。因此，对IR的突变反应至少部分取决于特异性修复途径和其他发育调节表型（如有丝分裂指数）的可用性。(C)2007 Elsevier B.V.保留所有权利。
There are a variety of mechanisms and pathways whereby cells safeguard their genomes in the face of environmental insults that damage DNA. Whether each of these pathways is equally robust at specific developmental stages in mammals and whether they are also modulated in a tissue-specific manner, however, are unclear. Here, we report that ionizing radiation (IR) produces different types of somatic mutations in fetal cells compared with adult cells of the same lineage. While 1 Gy of X-ray significantly induced intragenic point mutations in T cells of adult mice, no point mutational effect was observed when applied to fetuses. Fetal exposure to IR, on the other hand, led to a significant elevation of mitotic recombination in T cells, which was not observed in adults. Base excision repair (BER) activity was significantly lower in fetal hematopoietic cells than in adult cells, due to a low level of DNA polymerase p, the rate-limiting enzyme in BER. In fetal hematopoietic cells, this low BER activity, together with a high rate of proliferation, causes X-ray-induced DNA lesions, such as base damage, single strand breaks and double strand breaks, to be repaired by homologous recombination, which we observe as mitotic recombination. Higher BER activity and a relatively lower rate of cell proliferation likely contribute to the significant induction of DNA point mutations in adults. Thus, the mutational response to IR is at least partly determined by the availability of specific repair pathways and other developmentally regulated phenotypes, such as mitotic index. (C) 2007 Elsevier B.V. All rights reserved.