Previously we showed that human monocytes isolated from peripheral blood display downregulation of several DNA repair proteins, including XRCC1, ligase III, PARP-1 and DNA-PK_CS, resulting in a deficiency of DNA repair, while in macrophages derived from monocytes the repair protein expression and DNA repair is restored. To see whether this is a specific phenomenon of human monocytes and macrophages, we assessed the expression of these repair genes in mice. We also addressed the question at which differentiation step in bone marrow cells downregulation of DNA repair gene expression occurs. The study revealed that mouse monocytes, similar to human, lack the expression of XRCC1, ligase III, PARP-1 and DNA-PK_CS. If mice were treated with total body irradiation, they showed significant apoptosis in bone marrow monocytes, but not in peritoneal macrophages. This was also observed after treatment with the methylating anticancer drug temozolomide, resulting in high death rate of monocytes, but not macrophages. Monocytes arise from hematopoietic stem cells. Even the early stem cell fraction (LT-HSC) expressed detectable amounts of XRCC1, which was transiently upregulated, achieving the highest expression level in CMP (common myeloid progenitor) and, during the subsequent differentiation process, downregulated up to a non-detectable level in monocytes. The immediate monocyte precursor GMP also expressed ligase III, PARP-1 and DNA-PK_CS. All these repair genes lacking in monocytes were upregulated again in macrophages. The sensitivity of monocytes, macrophages and precursor cells roughly correlated with their XRCC1 expression level. Monocytes, but not macrophages, also displayed strong γH2AX focal staining, indicating the presence of non-repaired DNA double-strand breaks following total body irradiation. Overall, the data revealed that murine monocytes exhibit the same DNA repair-impaired phenotype and high sensitivity compared to macrophages as observed in human. Therefore, the repair deficiency previously described for human monocytes appears to be a general property of this cell type.

以前我们发现从外周血中分离的人类单核细胞显示出几种 DNA 修复蛋白的下调，包括 XRCC1、连接酶 III、PARP-1 和 DNA-PK _CS，导致 DNA 修复不足，而在源自单核细胞的巨噬细胞中，修复蛋白表达和 DNA 修复恢复。为了了解这是否是人类单核细胞和巨噬细胞的特定现象，我们评估了这些修复基因在小鼠中的表达。我们还解决了骨髓细胞中 DNA 修复基因表达下调发生的分化步骤的问题。研究表明，小鼠单核细胞与人类相似，缺乏 XRCC1、连接酶 III、PARP-1 和 DNA-PK _{CS 的表达}. 如果用全身照射处理小鼠，它们在骨髓单核细胞中显示出显着的细胞凋亡，但在腹膜巨噬细胞中没有。这在用甲基化抗癌药物替莫唑胺治疗后也观察到，导致单核细胞的高死亡率，但不是巨噬细胞。单核细胞来自造血干细胞。即使是早期干细胞部分 (LT-HSC) 也表达了可检测量的 XRCC1，它被瞬时上调，在 CMP（常见髓系祖细胞）中达到最高表达水平，并且在随后的分化过程中，下调至不可检测的水平在单核细胞中。直接单核细胞前体 GMP 也表达连接酶 III、PARP-1 和 DNA-PK _CS. 所有这些缺乏单核细胞的修复基因在巨噬细胞中再次上调。单核细胞、巨噬细胞和前体细胞的敏感性与其 XRCC1 表达水平大致相关。单核细胞，但不是巨噬细胞，也显示出强烈的 γH2AX 局部染色，表明全身照射后存在未修复的 DNA 双链断裂。总体而言，数据显示，与在人类中观察到的巨噬细胞相比，鼠单核细胞表现出相同的 DNA 修复受损表型和高敏感性。因此，先前描述的人类单核细胞修复缺陷似乎是这种细胞类型的一般特性。