hCINAP regulates the DNA-damage response and mediates the resistance of acute myelocytic leukemia cells to therapy.

Authors：Xu, Ruidan; Yu, Shuyu; Zhu, Dan; Huang, Xinping; Xu, Yuqi; Lao, Yimin; Tian, Yonglu; Zhang, Jinfang; Tang, Zefang; Zhang, Zemin; Yi, Jing; Zhu, Hong Hu; Zheng, Xiaofeng^*

Source：Nature Communications, 2019, 10(1): 3812.

DOI：10.1038/s41467-019-11795-5

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.