PARP-2 sustains erythropoiesis in mice by limiting replicative stress in erythroid progenitors.
PARP-2 sustains erythropoiesis in mice by limiting replicative stress in erythroid progenitors.
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DOI：
10.1038/cdd.2014.202
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发表时间：
2015-07
影响因子：
12.4
通讯作者：
Yélamos J
中科院分区：
文献类型：
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作者：
Farrés J;Llacuna L;Martin-Caballero J;Martínez C;Lozano JJ;Ampurdanés C;López-Contreras AJ;Florensa L;Navarro J;Ottina E;Dantzer F;Schreiber V;Villunger A;Fernández-Capetillo O;Yélamos J
红细胞生成是一个受到严格调控的过程，在这个过程中，多潜能造血干细胞产生成熟的红细胞。本研究表明，尽管血浆促红细胞生成素水平升高，但小鼠体内聚（adp -核糖）聚合酶2 （PARP-2）的缺失会导致慢性贫血，这种现象在缺乏PARP-1的小鼠中没有观察到。PARP-2的缺失导致红细胞寿命缩短和红细胞祖细胞分化受损。在红母细胞中，PARP-2缺乏会引发复制应激，这可以通过微核的存在、s期细胞中γ-H2AX（磷酸化组蛋白H2AX）的积累以及组成性CHK1和复制蛋白A的磷酸化来证明。转录组分析显示，parp -2缺陷细胞中p53依赖的dna损伤反应通路被激活，最终导致细胞周期和细胞死亡调节因子上调，同时伴有G2/M阻滞和凋亡。引人注目的是，虽然促凋亡p53靶基因Puma的缺失恢复了parp -2缺陷小鼠的红细胞压差水平，但细胞周期调节因子和CDK抑制剂p21的缺失会加剧parp -2缺陷胚胎中受损的胎儿肝脏红细胞生成，从而导致围产期死亡。尽管parp -2缺陷小鼠表现出的贫血与生命相容，但当暴露于应激诱导的增强溶血时，小鼠会迅速死亡。我们的研究结果明确了PARP-2在红细胞生成中的重要作用，通过限制在p21缺失和溶血增强的情况下必不可少的复制应激，强调了设计和使用特异性灭活PARP蛋白的PARP抑制剂可能产生的潜在影响。
Erythropoiesis is a tightly regulated process in which multipotential hematopoietic stem cells produce mature red blood cells. Here we show that deletion of poly(ADP-ribose) polymerase-2 (PARP-2) in mice leads to chronic anemia at steady state, despite increased erythropoietin plasma levels, a phenomenon not observed in mice lacking PARP-1. Loss of PARP-2 causes shortened lifespan of erythrocytes and impaired differentiation of erythroid progenitors. In erythroblasts, PARP-2 deficiency triggers replicative stress, as indicated by the presence of micronuclei, the accumulation of γ-H2AX (phospho-histone H2AX) in S-phase cells and constitutive CHK1 and replication protein A phosphorylation. Transcriptome analyses revealed the activation of the p53-dependent DNA-damage response pathways in PARP-2-deficient cells, culminating in the upregulation of cell-cycle and cell death regulators, concomitant with G2/M arrest and apoptosis. Strikingly, while loss of the proapoptotic p53 target gene Puma restored hematocrit levels in the PARP-2-deficient mice, loss of the cell-cycle regulator and CDK inhibitor p21 leads to perinatal death by exacerbating impaired fetal liver erythropoiesis in PARP-2-deficient embryos. Although the anemia displayed by PARP-2-deficient mice is compatible with life, mice die rapidly when exposed to stress-induced enhanced hemolysis. Our results pinpoint an essential role for PARP-2 in erythropoiesis by limiting replicative stress that becomes essential in the absence of p21 and in the context of enhanced hemolysis, highlighting the potential effect that might arise from the design and use of PARP inhibitors that specifically inactivate PARP proteins.