Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality.
Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality.
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DOI：
10.1038/ncomms9548
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发表时间：
2015-10-12
影响因子：
16.6
通讯作者：
Méndez J
中科院分区：
文献类型：
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作者：
Alvarez S;Díaz M;Flach J;Rodriguez-Acebes S;López-Contreras AJ;Martínez D;Cañamero M;Fernández-Capetillo O;Isern J;Passegué E;Méndez J
胚胎发育过程中的复制性压力会影响成年人的衰老和疾病易感性。G1期的数千个起源被许可，这些起源不一定在随后的S期被激活，从而提供了一种对抗复制应激的保护机制。这些“休眠”的起源提供了一个备份，在存在停滞的叉，并可能赋予灵活性的复制程序在特定的细胞类型在分化过程中，一个角色，仍然是未开发的。在这里，我们表明，使用一个小鼠品系与亚型表达的起源许可因子微型染色体维持（MCM）3，限制在体内的起源许可影响造血干细胞的功能和分化的快速分裂的红细胞前体。Mcm3缺陷型成红细胞显示异常的DNA复制模式，不能完全成熟，导致致命性贫血。我们的研究结果表明，造血祖细胞是特别敏感的复制压力，和完整的原产地许可，确保其正确的分化和功能。 什么原因导致造血干细胞功能丧失？在这里，Alvarez等人表明，来源许可因子MCM3的丢失诱导复制应激（RS），导致异常的红细胞成熟，但对RS具有较高耐受性的小鼠品系可以克服这一缺陷。
Replicative stress during embryonic development influences ageing and predisposition to disease in adults. A protective mechanism against replicative stress is provided by the licensing of thousands of origins in G1 that are not necessarily activated in the subsequent S-phase. These ‘dormant' origins provide a backup in the presence of stalled forks and may confer flexibility to the replication program in specific cell types during differentiation, a role that has remained unexplored. Here we show, using a mouse strain with hypomorphic expression of the origin licensing factor mini-chromosome maintenance (MCM)3 that limiting origin licensing in vivo affects the functionality of hematopoietic stem cells and the differentiation of rapidly-dividing erythrocyte precursors. Mcm3-deficient erythroblasts display aberrant DNA replication patterns and fail to complete maturation, causing lethal anemia. Our results indicate that hematopoietic progenitors are particularly sensitive to replication stress, and full origin licensing ensures their correct differentiation and functionality. What causes hematopoietic stem cell loss of functionality? Here, Alvarez et al. show that loss of origin licensing factor MCM3 induces replicative stress (RS), causing aberrant erythrocyte maturation, but mice strains with higher tolerance to RS can overcome this defect.