miR-18a impairs DNA damage response through downregulation of ataxia telangiectasia mutated (ATM) kinase.
miR-18a impairs DNA damage response through downregulation of ataxia telangiectasia mutated (ATM) kinase.
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miR-18a 通过下调共济失调毛细血管扩张突变 (ATM) 激酶来损害 DNA 损伤反应
DOI：
10.1371/journal.pone.0025454
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Song L;Lin C;Wu Z;Gong H;Zeng Y;Wu J;Li M;Li J
DNA损伤反应(DDR)包括多个步骤，通过细胞进化来感知DNA损伤，转导信号并启动DNA损伤的修复。共济失调毛细血管扩张突变(ATM)激酶作为DNA损伤信号的主要传感器和转导，已被证明在DDR和癌症预防中发挥着重要作用。因此，了解ATM调控的分子机制引起了人们的极大关注。在这里，我们发现miR-18a在乳腺癌细胞系和患者组织样本中都上调。此外，我们还证明了异位表达miR-18a通过直接靶向ATM-3‘-UTR而下调ATM的表达，并取消了IR诱导的细胞周期停滞。与ATM siRNA的作用类似，在乳腺癌细胞中过表达miR-18a会降低损伤修复能力和基于同源重组的DNA修复效率，并使细胞对γ辐射(IR)增敏。然而，抑制miR-18a导致DNA损伤修复增强，HRR效率增加，细胞辐射敏感性降低。此外，我们还发现，在miR-18a过表达的细胞中，ATM激酶下游底物H_2AX和53BP1的磷酸化水平和核焦点形成显著降低。综上所述，我们的结果揭示了ATM表达的一种新的调控机制，并表明miR-18a可能是一个新的治疗靶点。
The DNA damage response (DDR) encompasses multi-step processes by which cells evolve to sense DNA damage, transduce the signal and initiate the repair of damaged DNA. Ataxia Telangiectasia Mutated (ATM) Kinase, which functions as the primary sensor and transducer of DNA damage signal, has been demonstrated to play an important role in the DDR and cancer prevention. Hence, understanding the molecular mechanisms underlying the regulation of ATM has received much attention. Here, we found that miR-18a was upregulated in both cell lines and patients' tissue samples of breast cancer. Furthermore, we demonstrated that ectopically expressing miR-18a downregulated ATM expression by directly targeting the ATM-3′-UTR and abrogated the IR-induced cell cycle arrest. Similar to the effect of ATM siRNA, overexpressing miR-18a in breast cancer cells reduced the DNA damage repair ability and the efficiency of homologous recombination-based DNA repair (HRR) and sensitized cells to γ-irradiation (IR) treatment. However, inhibition of miR-18a led to augmentation of DNA damage repair, increase of HRR efficiency and reduced cellular radiosensitivity. Moreover, we showed that the phorsphorylation level and nuclear foci formation of H2AX and 53BP1, the downstream substrates of ATM kinase, were significantly deceased in miR-18a overexpressing cells. Taken together, our results uncover a new regulatory mechanism of ATM expression and suggest that miR-18a might be a novel therapeutic target.
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影响因子：
4.8
作者：
Chen, Benjamin P. C.;Uematsu, Naoya;Chen, David J.
通讯作者：
Chen, David J.
影响因子：
56.9
作者：
Celeste, A;Petersen, S;Nussenzweig, A
通讯作者：
Nussenzweig, A
DOI：
10.1083/jcb.200510130
发表时间：
2006-04-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bekker-Jensen S;Lukas C;Kitagawa R;Melander F;Kastan MB;Bartek J;Lukas J
通讯作者：
Lukas J
影响因子：
10.5
作者：
Mills, KD;Ferguson, DO;Alt, FW
通讯作者：
Alt, FW
影响因子：
3.4
作者：
Boultwood, J
通讯作者：
Boultwood, J