RELA/ LncRNA-uc002jit.1/PARP1形成环路调节DNA修复对DNA损伤药物清除白血病干细胞的影响

损伤DNA是多数抗癌药物共同的机制，DNA修复能力增强可致肿瘤耐药。PARP1可感知DNA损伤并通过PAR 化组装ATM/PIASy /IKKγ复合体，进而激活NF-κB。但是，NF-κB被DNA损伤特异性激活后如何参与DNA修复？仍然未知。我们研究表明NF-κB/RELA参与急性髓细胞白血病（AML）细胞DNA修复，并与调控PARP1的转录有关，而且可能是由长链非编码RNA（LncRNA） uc002jit.1介导的；抑制PARP1可降低NF-κB活性和DNA修复能力。由此，我们设想 RELA/ LncRNA-uc002jit.1/PARP1可能形成环路调节DNA修复。因此本课题拟从分子、细胞和动物水平探讨该环路各个分子之间具体作用位点及机制，以彻底阐明NF-κB被DNA损伤特异性激活后参与DNA修复的分子机制，以及阻断该环路能否增加AML干细胞对DNA损伤药物和PARP1抑制剂的敏感。

DNA damage is a common mechanism for most anticancer drugs. The enhancement of DNA repair ability can lead to the drug resistance. When DNA is damaged, PARP1 can perceive and assemble the ATM/PIASy /IKK gamma complex by inducing PARylation, and then activate NF- kappa B. However, how do specifically activated NF- kappa B participate in DNA repair after DNA damage? It's still unknown. Our previous studies demonstrated that NF- kappa B/RELA participate in DNA repair in acute myeloid leukemia (AML) cells, which is related to its regulation of the transcription of PARP1, moreover, this process may be mediated by long non-coding RNA（LncRNA ）uc002jit.1.; moreover, inhibition of PARP1 can downregulate NF- kappa B activity and DNA damage repair capacity. Therefore, we assume that RELA/LncRNA-uc002jit.1/PARP1 may form a loop regulating DNA repair. Based on these findings, we intend to explore the specific interaction sites of each molecular in the loop from molecular, cellular and animal level, and to thoroughly clarify the molecular mechanism that how do specifically activated NF- kappa B regulate DNA repair after DNA damage; furthermore, whether blocking the loop can increase AML stem cell sensitivity to DNA damage agents and PARP1 inhibitors.