Impaired DNA repair in mouse monocytes compared to macrophages and precursors.
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-PKCS, 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-PKCS. 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-PKCS. 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.
['Berte|Nancy|N|', 'Eich|Marcus|M|', 'Heylmann|Daniel|D|', 'Koks|Carolien|C|', 'Van Gool|Stefaan W|SW|', 'Kaina|Bernd|B|']
D000818:Animals D017209:Apoptosis D004247:DNA D053903:DNA Breaks, Double-Stranded D004249:DNA Damage D000072481:DNA Ligase ATP D004260:DNA Repair D051747:DNA-Activated Protein Kinase D004268:DNA-Binding Proteins D005260:Female D005720:Gamma Rays D005786:Gene Expression Regulation D006657:Histones D008264:Macrophages D051379:Mice D008810:Mice, Inbred C57BL D009000:Monocytes D000071137:Poly (ADP-Ribose) Polymerase-1 D000075223:Poly-ADP-Ribose Binding Proteins D013234:Stem Cells D000077204:Temozolomide D000076105:X-ray Repair Cross Complementing Protein 1
Monocytes Macrophages Stem cells Genotoxicants Monocyte maturation