The DNA damage response pathway in normal hematopoiesis and malignancies
The DNA damage response pathway in normal hematopoiesis and malignancies
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DOI：
10.1007/s12185-017-2300-7
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发表时间：
2017-09-01
影响因子：
2.1
通讯作者：
Mizutani, Shuki
中科院分区：
文献类型：
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作者：
Delia, Domenico;Mizutani, Shuki
在哺乳动物细胞中，DNA 损伤反应 (DDR) 可以防止 DNA 错误复制和传播到下一代，从而保持基因组稳定性。 DDR 的核心是相关信号激酶 ATM、ATR 和 DNA-PK，它们调节 DNA 修复和相关事件，如细胞周期检查点、染色质重塑、转录和最终的细胞凋亡。多项研究结果强调了造血干细胞 (HSC) 中 DDR 的发生，并且这些细胞中 DNA 损伤的持续存在会促进其功能衰退和白血病突变的积累。除了有利于肿瘤的形成和进展之外，直接或间接使某些 DDR 通路失活的分子缺陷可以提供治疗机会，因为修复 DNA 损伤的能力降低使得造血系统恶性肿瘤容易受到基因毒性药物的影响，这些药物也通过合成致死相互作用发挥作用。在这里，我们讨论 DDR 在 HSC 维持和预防白血病发生中的重要作用，以及如何有效利用获得性 DDR 功能障碍或阻断该途径的药物来治疗各种造血系统恶性肿瘤。
In mammalian cells, the DNA damage response (DDR) prevents the replication and propagation of DNA errors to the next generation, thus maintaining genomic stability. At the heart of the DDR are the related signaling kinases ATM, ATR, and DNA-PK, which regulate DNA repair and associated events such as cell cycle checkpoints, chromatin remodeling, transcription, and ultimately apoptosis. Several findings highlight the occurrence of DDR in hemopoietic stem cells (HSCs), and persistence of DNA lesions in these cells promotes their functional decline and accumulation of leukemogenic mutations. Besides favoring tumor formation and progression, molecular defects that directly or indirectly inactivate certain DDR pathways can provide a therapeutic opportunity, since a reduced ability to repair DNA lesions renders hemopoietic malignancies vulnerable to genotoxic drugs acting also through synthetic lethal interactions. Here, we discuss the essential role of DDR in HSC maintenance and protection against leukemogenesis, and how acquired DDR dysfunctions or pharmacological agents that block this pathway can be effectively exploited for the treatment of various hematopoietic malignancies.