Homologous recombination as a resistance mechanism to replication-induced double-strand breaks caused by the antileukemia agent CNDAC
Homologous recombination as a resistance mechanism to replication-induced double-strand breaks caused by the antileukemia agent CNDAC
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DOI：
10.1182/blood-2009-05-220376
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发表时间：
2010-09-09
期刊：
影响因子：
20.3
通讯作者：
Plunkett, William
中科院分区：
文献类型：
--
作者：
Liu, Xiaojun;Wang, Yaqing;Plunkett, William
核苷类似物2 '-C-氰基-2'-脱氧-1-β-D-阿拉伯呋喃戊糖基胞嘧啶（CNDAC）目前正在进行血液恶性肿瘤的临床试验，其作用机制是在掺入DNA后引起单链断裂。随后在体内产生双链断裂（DSB），并且如果不修复，则对细胞存活造成致命影响。本研究旨在确定CNDAC诱导的DSB形成和修复的机制。我们证明了当细胞进入随后的S期时，由CNDAC掺入DNA诱导的单链断裂转化为DSB。CNDAC诱导的DSB是复制的产物，而不是凋亡的结果。ATM是同源重组（HR）的激活剂，在细胞系和原发性急性髓性白血病样品中CNDAC处理后，ATM对细胞存活至关重要，HR组分Rad 51、Xrcc 3和Brca 2也是如此。此外，在CNDAC处理的细胞进入第二个复制周期后，姐妹染色单体交换（HR的标志）的形成显著增加。与此相反，无论是复制应激传感器ATR还是DNA-PK，非同源末端连接的DSB的启动子，都不参与CNDAC诱导的损伤的修复。总之，这些结果表明，HR，而不是非同源末端连接，是CNDAC引起的DNA损伤的主要修复或存活机制。（血。2010; 116（10）：1737-1746）
The nucleoside analog 2'-C-cyano-2'-deoxy- 1-beta-D-arabino-pentofuranosylcytosine (CNDAC), currently in clinical trials for hematologic malignancies, has a novel action mechanism of causing a single-strand break after its incorporation into DNA. Double-strand breaks (DSBs) are generated thereafter in vivo and, if not repaired, pose lethal impact on cell survival. This study sought to define the mechanisms by which CNDAC-induced DSBs are formed and repaired. We demonstrated that single-strand breaks induced by CNDAC incorporation into DNA were converted to DSBs when cells progressed into the subsequent S-phase. CNDAC-induced DSBs were products of replication, rather than a consequence of apoptosis. ATM, the activator of homologous recombination (HR), was essential for cell survival after CNDAC treatment in cell lines and in primary acute myeloid leukemia samples, as were the HR components, Rad51, Xrcc3, and Brca2. Furthermore, formation of sister chromatid exchanges, a hallmark of HR, increased significantly after CNDAC-treated cells had progressed into a second replication cycle. In contrast, neither the replication stress sensor ATR nor DNA-PK, the initiator of nonhomologous end-joining of DSB, was involved in repair of CNDAC-induced damage. Together, these results indicate that HR, but not nonhomologous end-joining, is the major repair or survival mechanism for DNA damage caused by CNDAC. (Blood. 2010; 116(10):1737-1746)