The role of the novel LincRNA uc002jit.1 in NF-kB-mediated DNA damage repair in acute myeloid leukemia cells
The role of the novel LincRNA uc002jit.1 in NF-kB-mediated DNA damage repair in acute myeloid leukemia cells
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DOI：
10.1016/j.yexcr.2020.111985
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发表时间：
2020-06-15
影响因子：
3.7
通讯作者：
Wu, Lixian
中科院分区：
文献类型：
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作者：
Li, Ding;Yu, Zelei;Wu, Lixian
长链非编码RNA（lncRNA）在急性髓系白血病（AML）中的作用及其治疗潜力已引起越来越多的关注。然而，许多lncRNA尚未在AML中注释，其对AML治疗的预测价值仍不清楚。在这项研究中，我们确定了一个新的大型基因间非编码RNA uc002jit.1（D43770）从lncRNA微阵列。我们首次证明uc002jit.1是核因子κ B/RELA的靶基因，RELA通过与其启动子结合来调控uc002jit.1的转录。此外，uc002jit.1敲低损害了聚（ADP-核糖）聚合酶1（PARP 1）mRNA的稳定性，然后降低DNA损伤后PARP 1蛋白含量和PAR化水平，从而抑制AML细胞中DNA损伤修复。此外，uc002jit.1敲除可显着抑制AML细胞增殖，并增加体外和体内小鼠模型对化疗药物的敏感性。总之，我们的研究表明uc002jit.1可能与AML的发生和预后相关，并可能成为AML的新的诊断/预后生物标志物和治疗靶点。
The roles and therapeutic potential of long noncoding RNAs (lncRNAs) in acute myeloid leukemia (AML) have attracted increased attention. However, many lncRNAs have not been annotated in AML, and their predictive value for AML therapy remains unclear. In this study, we identified a novel large intergenic noncoding RNA uc002jit.1 (D43770) from a lncRNA microarray. We first proved uc002jit.1 is a target gene of nuclear factor kappa B/RELA, RELA regulated uc002jit.1 transcription by binding to its promoter. Additionally, uc002jit.1 knockdown impaired the stability of poly (ADP-ribose) polymerase 1 (PARP1) mRNA, and then reduced PARP1 protein content and PARylation level upon DNA damage, thus inhibiting DNA damage repair in AML cells. Moreover, uc002jit.1 knockdown significantly inhibited AML cells proliferation and increased the sensitivity to chemotherapeutic drugs in vitro as well as in a mouse model in vivo. Overall, our study indicated that uc002jit.1 may be associated with the occurrence and prognosis of AML and could be a new diagnostic/prognostic biomarker and therapeutic target for AML.