KU70 Inhibition Impairs Both Non-Homologous End Joining and Homologous Recombination DNA Damage Repair Through SHP-1 Induced Dephosphorylation of SIRT1 in Adult T-Cell Leukemia-Lymphoma Cells

Cellular Physiology and Biochemistry

Wenlei Yu¹ 

关键词: Ku70;    SHP-1;    SIRT1;    DNA damage repair;    Non-homologous end joining Homologous recombination;   

DOI  :  10.1159/000493815

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background/Aims Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease which is highly resistant to chemotherapy. Studies show that enhanced ability of DNA damage repair (DDR) in cancer cells plays a key role in chemotherapy resistance. Here, we suggest that defect in DDR related genes might be a promising target to destroy the genome stability of tumor cells. Methods Since KU70 is highly expressed in Jurkat cells, one of the most representative cell lines of ATL, we knocked down KU70 by shRNA and analyzed the impact of KU70 deficiency in Jurkat cells as well as in NOD-SCID animal models by western blot, immunofluorescence, flow cytometry and measuring DNA repair efficiency. Results It is observed that silencing of KU70 resulted in accumulated DNA damage and impaired DDR in Jurkat cells, resulting in more apoptosis, decreased cell proliferation and cell cycle arrest. DNA damage leads to DNA double-strand breaks (DSBs), which are processed by either non-homologous end joining(NHEJ) or homologous recombination(HR). In our study, both NHEJ and HR are impaired because of KU70 defect, accompanied with increased protein level of SHP-1, a dephosphorylation enzyme. In turn, SHP-1 led to dephosphorylation of SIRT1, which further impaired HR repair efficiency. Moreover, KU70 deficiency prolonged survival of Jurkat-xenografted mice. Conclusion These findings suggest that targeting KU70 is a promising target for ATL and might overcome the existing difficulties in chemotherapy.

【 授权许可】

CC BY-NC-ND