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

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

doi:10.1038/s41467-019-11795-5

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.

Highlights

Acute myeloid leukemia (AML) is a genetically heterogeneous malignant disorder of the hematopoietic system, characterized by the accumulation of DNA-damaged immature myeloid precursors
To explore whether Human coilin-interacting nuclear ATPase protein (hCINAP) is involved in the DNA-damage response (DDR), U2OS cells were treated with ionizing radiation (IR) to induce double strand break (DSB)
Consistent with these observations, nuclear hCINAP increased, whereas cytoplasmic hCINAP decreased following IR treatment (Fig. 1c). These results indicated that hCINAP functions in a spatiotemporal manner in the process of DNA repair

Summary

Introduction

Acute myeloid leukemia (AML) is a genetically heterogeneous malignant disorder of the hematopoietic system, characterized by the accumulation of DNA-damaged immature myeloid precursors. We find that hCINAP is involved in the repair of double-stranded DNA breaks (DSB) and that its expression correlates with AML prognosis. 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. In response to DNA-damage, a series of repair proteins sequentially accumulate at the damaged site and function to induce signal transduction pathways that initiate the subsequent repair of DSB2. These proteins are finely modulated by dynamic and reversible posttranslational modifications. The cellular effectors influencing these two repair pathways in AML have not been clearly identified[15]

Methods

Results

Conclusion