Loss of the homologous recombination gene rad51 leads to Fanconi anemia-like symptoms in zebrafish
Loss of the homologous recombination gene rad51 leads to Fanconi anemia-like symptoms in zebrafish
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DOI：
10.1073/pnas.1620631114
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发表时间：
2017-05-30
影响因子：
11.1
通讯作者：
Cvejic, Ana
中科院分区：
文献类型：
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作者：
Botthof, Jan Gregor;Bielczyk-Maczynska, Ewa;Cvejic, Ana
RAD51是一种不可缺少的同源重组蛋白，是链侵入和交换所必需的。它最近被指定为范可尼贫血（FA）基因，在发现两名患者携带显性阴性突变后。FA是一种遗传性DNA修复障碍，其特征在于各种先天性异常、进行性骨髓衰竭和癌症易感性。在这份报告中，我们描述了一个可行的脊椎动物模型的RAD 51损失。斑马鱼rad51功能丧失突变体开发FA的关键特征，包括细胞减少的肾骨髓，对交联剂的敏感性，以及尺寸减小。我们发现，这些症状中的一些干细胞增殖减少和胚胎造血干细胞和祖细胞凋亡增加。p53的突变能够挽救在单个突变体中观察到的造血缺陷，但导致肿瘤发展。我们进一步证明，长期的炎症应激可加重血液损伤，导致肾骨髓细胞数量的额外减少。这些研究结果加强了RAD51作为Fanconi基因的分配，并为胚胎发生过程中异常的p53信号传导导致FA后期出现血液学缺陷的概念提供了更多的证据。对这种斑马鱼FA模型的进一步研究将有助于更深入地了解FA中骨髓衰竭的分子基础和RAD 51的细胞作用。
RAD51 is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anemia (FA) gene, following the discovery of two patients carrying dominant-negative mutations. FA is a hereditary DNA-repair disorder characterized by various congenital abnormalities, progressive bone marrow failure, and cancer predisposition. In this report, we describe a viable vertebrate model of RAD51 loss. Zebrafish rad51 loss-of-function mutants developed key features of FA, including hypocellular kidney marrow, sensitivity to cross-linking agents, and decreased size. We show that some of these symptoms stem from both decreased proliferation and increased apoptosis of embryonic hematopoietic stem and progenitor cells. Comutation of p53 was able to rescue the hematopoietic defects seen in the single mutants, but led to tumor development. We further demonstrate that prolonged inflammatory stress can exacerbate the hematological impairment, leading to an additional decrease in kidney marrow cell numbers. These findings strengthen the assignment of RAD51 as a Fanconi gene and provide more evidence for the notion that aberrant p53 signaling during embryogenesis leads to the hematological defects seen later in life in FA. Further research on this zebrafish FA model will lead to a deeper understanding of the molecular basis of bone marrow failure in FA and the cellular role of RAD51.