BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint
BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint
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DOI：
10.1016/s1535-6108(04)00056-x
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发表时间：
2004-03-01
期刊：
影响因子：
50.3
通讯作者：
Carroll, M
中科院分区：
文献类型：
--
作者：
Dierov, J;Dierova, R;Carroll, M
慢性粒细胞白血病（CIVIL）是一种与BCR/ABL酪氨酸激酶蛋白表达相关的两阶段疾病。然而，BCR/ABL表达是否直接导致胚泡危象，如果是这样，通过什么机制，是未知的。我们已经发现，BCR/ABL易位后，从细胞质到细胞核的遗传毒性的压力。此外，BCR/ABL增加了依托泊苷治疗后的DNA双链损伤，并导致S期内检查点的缺陷，导致放射抗性DNA合成（RDS）表型。在细胞核中，BCR/ABL与共济失调-毛细血管扩张和rad 3相关蛋白（ATR）相关，并破坏ATR依赖的信号转导。ATR在BCR/ABL表达细胞系中的过表达纠正了DNA损伤表型。这些结果表明BCR/ABL在改变细胞对DNA损伤的反应中的核作用。
Chronic myelogeneous leukemia (CIVIL) is a two-stage disease associated with expression of the BCR/ABL tyrosine kinase protein. However, whether BCR/ABL expression directly causes blast crisis, and if so by what mechanism, is unknown. We have found that BCR/ABL translocates from the cytoplasm to the nucleus after genotoxic stress. Furthermore, BCR/ABL increases DNA double-strand damage after etoposide treatment and leads to a defect in an intra-S phase checkpoint, causing a radioresistant DNA synthesis (RDS) phenotype. In the nucleus, BCR/ABL associates with the ataxia-telangiectasia and rad 3-related protein (ATR) and disrupts ATR-dependent signal transduction. Overexpression of ATR in a BCR/ABL-expressing cell line corrects the DNA damage phenotype. These results demonstrate a nuclear role for BCR/ABL in altering the cellular response to DNA damage.