c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias.
c-MYC Generates Repair Errors via Increased Transcription of Alternative-NHEJ Factors, LIG3 and PARP1, in Tyrosine Kinase-Activated Leukemias.
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DOI：
10.1158/1541-7786.mcr-14-0422
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Rassool FV
中科院分区：
文献类型：
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作者：
Muvarak N;Kelley S;Robert C;Baer MR;Perrotti D;Gambacorti-Passerini C;Civin C;Scheibner K;Rassool FV
表达组成型激活酪氨酸激酶（TK）BCR-ABL 1和FLT 3/ITD的白血病激活信号通路，通过产生活性氧（ROS）、DNA双链断裂（DSB）和易错修复增加基因组不稳定性。非同源末端连接（NHEJ）途径是DSB修复的主要途径，在TK激活的白血病中高度异常; NHEJ的另一种形式（ALT-NHEJ）占主导地位，表现为DNA连接酶IIIα（LIG 3）和聚（ADP-核糖）聚合酶（PARP 1）表达增加、大基因组缺失频率增加以及使用DNA序列微同源性进行修复。这项研究首次证明TK靶点c-MYC在LIG 3和PARP 1的转录激活和随后的表达中起作用，并有助于在TK激活的白血病中观察到的易错修复增加。c-MYC负调节microRNA miR-150和miR-22，其在原代和培养的白血病细胞和慢性髓细胞性白血病（CML）人类患者样品中显示与LIG 3和PARP 1表达负相关。值得注意的是，c-MYC的抑制和miR-150和-22的过表达降低了ALT-NHEJ活性。因此，BCR-ABL 1或FLT 3/ITD诱导c-MYC表达，通过产生修复错误的ALT-NHEJ修复因子的增强表达导致基因组不稳定。
Leukemias expressing the constitutively activated tyrosine kinases (TKs) BCR-ABL1 and FLT3/ITD activate signaling pathways that increase genomic instability through generation of reactive oxygen species (ROS), DNA double-strand breaks (DSBs) and error-prone repair. The non-homologous end-joining (NHEJ) pathway is a major pathway for DSB repair and is highly aberrant in TK-activated-leukemias; an alternative form of NHEJ (ALT-NHEJ) predominates, evidenced by increased expression of DNA ligase IIIα (LIG3) and poly (ADP-ribose) polymerase (PARP1), increased frequency of large genomic deletions, and repair using DNA sequence microhomologies. This study, for the first time, demonstrates that the TK target c-MYC plays a role in transcriptional activation and subsequent expression of LIG3 and PARP1 and contributes to the increased error-prone repair observed in TK-activated leukemias. c-MYC negatively regulates microRNAs miR-150 and miR-22 which demonstrate an inverse correlation with LIG3 and PARP1 expression in primary and cultured leukemia cells and chronic myelogenous leukemia (CML) human patient samples. Notably, inhibition of c-MYC and overexpression of miR-150 and -22 decreases ALT-NHEJ activity. Thus, BCR-ABL1 or FLT3/ITD induces c-MYC expression leads to genomic instability via augmented expression of ALT-NHEJ repair factors that generate repair errors.