Erratum: BRIT1/MCPH1 Expression in Chronic Myeloid Leukemia and Its Regulation of the G2/M Checkpoint

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（即hTERT表达的BRCT重复序列抑制剂，BRCT-repeat inhibitor of hTERT expression）又名小头蛋白（MCPH1），是参与DNA修复、并作为细胞内S期与G2/M期检验点调控因子的关键基因，隶属于细胞生命活动的复杂调控网络。BRIT1/MCPH1在细胞周期进程调控中的核心作用，集中体现于对G2/M期检验点的调控。研究发现，初诊慢性髓性白血病（chronic myeloid leukemia, CML）患者的K562细胞及外周血细胞中，BRIT1/MCPH1的表达水平呈下调状态，但本研究未观察到bcr/abl活性与BRIT1/MCPH1表达水平存在任何相关性。为探究CML细胞的基因组不稳定性，我们评估了此类细胞在暴露于已知遗传毒性试剂羟基脲（hydroxyurea）后阻滞有丝分裂的能力。实验结果显示，CML细胞未激活G2/M期细胞周期检验点阻滞通路与凋亡机制，仍可持续增殖，这种表型可能使细胞易于积累基因组缺陷。综上，本研究发现CML细胞中BRIT1/MCPH1表达水平低下，且G2/M期检验点阻滞功能存在缺陷，证实此类细胞存在结构性基因组不稳定性。