hCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy
hCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy
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DOI：
10.1038/s41467-019-11795-5
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发表时间：
2019-08
影响因子：
16.6
通讯作者：
Ruidan Xu;Shuyu Yu;Dan Zhu;Xinping Huang;Yuqi Xu;Yimin Lao;Yonglu Tian;Jinfang Zhang;Zefang Tang;Zemin Zhang;Jing Yi;Honghu Zhu;Xiaofeng Zheng
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文献类型：
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作者：
Ruidan Xu;Shuyu Yu;Dan Zhu;Xinping Huang;Yuqi Xu;Yimin Lao;Yonglu Tian;Jinfang Zhang;Zefang Tang;Zemin Zhang;Jing Yi;Honghu Zhu;Xiaofeng Zheng
急性髓性白血病（AML）是一种遗传异质性造血系统恶性疾病，其特征在于DNA损伤的未成熟髓样前体细胞的积累。在这里，我们发现hCINAP参与双链DNA断裂（DSB）的修复，其表达与AML预后相关。在DSB之后，hCINAP被募集到损伤位点，在那里它促进NPM 1的SENP 3依赖性去SUMO化。这又导致RAP 80从损伤位点解离以及CTIP依赖性DNA切除和同源重组。NPM1 SUMO化是在DNA损伤反应（DDR）早期招募DNA修复蛋白所必需的，SUMO化的NPM1影响BRCA1复合物的组装。hCINAP的敲低还使患者来源的异种移植物（PDX）小鼠模型对化疗敏感。在临床AML样品中，低hCINAP表达与患者的较高总体存活率相关。这些结果为hCINAP在DNA损伤反应过程中的功能及其在AML耐药治疗中的作用提供了机制性见解。
Acute myeloid leukemia (AML) is a genetically heterogeneous malignant disorder of the hematopoietic system, characterized by the accumulation of DNA-damaged immature myeloid precursors. Here, we find that hCINAP is involved in the repair of double-stranded DNA breaks (DSB) and that its expression correlates with AML prognosis. Following DSB, hCINAP is recruited to damage sites where it promotes SENP3-dependent deSUMOylation of NPM1. This in turn results in the dissociation of RAP80 from the damage site and CTIP-dependent DNA resection and homologous recombination. NPM1 SUMOylation is required for recruitment of DNA repair proteins at the early stage of DNA-damage response (DDR), and SUMOylated NPM1 impacts the assembly of the BRCA1 complex. Knockdown of hCINAP also sensitizes a patient-derived xenograft (PDX) mouse model to chemotherapy. In clinical AML samples, low hCINAP expression is associated with a higher overall survival rate in patients. These results provide mechanistic insight into the function of hCINAP during the DNA-damage response and its role in AML resistance to therapy.