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

Ruidan Xu, Shuyu Yu, Dan Zhu, Xinping Huang, Yuqi Xu, Yimin Lao, Yonglu Tian, Jinfang Zhang, Zefang Tang, Zemin Zhang, Jing Yi, Hong-Hu Zhu and Xiaofeng Zheng ()
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Ruidan Xu: Peking University
Shuyu Yu: Peking University
Dan Zhu: Peking University
Xinping Huang: Peking University
Yuqi Xu: Peking University
Yimin Lao: Shanghai Jiao Tong University School of Medicine
Yonglu Tian: Peking University
Jinfang Zhang: Peking University
Zefang Tang: Peking University
Zemin Zhang: Peking University
Jing Yi: Shanghai Jiao Tong University School of Medicine
Hong-Hu Zhu: Peking University
Xiaofeng Zheng: Peking University

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11795-5

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