Department of Clinical and Molecular Biomedicine, Section of Hematology, Ferrarotto Hospital, Via Citelli 6, Catania, Italy.
Acta Haematol. 2011;126(4):205-10. doi: 10.1159/000329911. Epub 2011 Sep 16.
BRIT1 (BRCT-repeat inhibitor of hTERT expression), also known as microcephalin (MCPH1), is a crucial gene in the complex cellular machine that is devoted to DNA repair and acts as a regulator of both the intra-S and G2/M checkpoints. The most important role of BRIT1/MCPH1 in the regulation of cell cycle progression appears to be the G2/M checkpoint. The K562 and peripheral blood cells of chronic myeloid leukemia (CML) patients at diagnosis were found to downregulate BRIT1/MCPH1. However, we could not find any correlation between bcr/abl activity and the BRIT1/MCPH1 level. In order to study the genomic instability of CML cells, we evaluated the ability of these cells to arrest mitotic division after exposure to hydroxyurea, a known genotoxic agent. We showed that CML cells continue to proliferate without the activation of the G2/M cell cycle checkpoint arrest or of the apoptotic mechanism. This behavior may predispose the cells to accumulate genomic defects. In conclusion, we found that CML cells have a low BRIT1/MCPH1 level and show a defective G2/M arrest, confirming that these cells have a constitutive genomic instability.
BRIT1（端粒酶表达的 BRCT 重复抑制剂），也称为 Microcephalin（MCPH1），是一种在专门从事 DNA 修复的复杂细胞机器中起关键作用的基因，同时作为细胞内 S 和 G2/M 检验点的调节剂。BRIT1/MCPH1 在调节细胞周期进程中的最重要作用似乎是 G2/M 检验点。在诊断时，慢性髓细胞白血病（CML）患者的 K562 和外周血细胞发现下调了 BRIT1/MCPH1。然而，我们没有发现 bcr/abl 活性与 BRIT1/MCPH1 水平之间的任何相关性。为了研究 CML 细胞的基因组不稳定性，我们评估了这些细胞在暴露于羟脲（一种已知的遗传毒性剂）后停止有丝分裂分裂的能力。我们表明，CML 细胞在没有激活 G2/M 细胞周期检验点阻滞或凋亡机制的情况下继续增殖。这种行为可能使细胞容易积累基因组缺陷。总之，我们发现 CML 细胞的 BRIT1/MCPH1 水平较低，并且显示出有缺陷的 G2/M 阻滞，这证实了这些细胞具有固有的基因组不稳定性。
