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Calcium influx-mediated translocation of m-calpain induces Ku80 cleavage and enhances the Ku80-related DNA repair pathway

 Kyung Hye Baek  ;  Han Vit Yu  ;  Eosu Kim  ;  Younghwa Na  ;  Youngjoo Kwon 
 ONCOTARGET , Vol.7(21) : 30831-30844, 2016 
Journal Title
Issue Date
Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Calcium/metabolism* ; Calcium Ionophores/pharmacology ; Calpain/genetics ; Calpain/metabolism* ; Cell Line ; Cell-Free System/metabolism ; DNA Breaks, Double-Stranded ; DNA End-Joining Repair/physiology* ; Drug Resistance, Neoplasm ; Epithelial Cells/drug effects ; Gene Knockdown Techniques ; Humans ; Ionomycin/pharmacology ; Ku Autoantigen/metabolism* ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy ; Protein Binding ; Protein Domains/physiology ; Protein Multimerization/physiology ; Protein Transport/physiology ; Proteolysis ; Proteomics ; RNA Interference ; RNA, Small Interfering ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
DNA damage ; Ku80-related DNA repair ; adriamycin ; m-calpain
Proteomic analysis of ionomycin-treated and untreated mammary epithelial MCF10A cells elucidated differences in Ku80 cleavage. Ku80, a subunit of the Ku protein complex, is an initiator of the non-homologous, end-joining (NHEJ), double-strand breaks (DSBs) repair pathway. The nuclear Ku80 was cleaved in a calcium concentration-dependent manner by m-calpain but not by m-calpain. The cleavage of nuclear Ku80 at its α/β domain was validated by Western blotting analysis using flag-tagged expression vectors of truncated versions of Ku80 and a flag antibody and was confirmed in m-calpain knock-down cells and in vitro cell-free evaluation with recombinant proteins of calpains, Ku70, and Ku80. In addition, the cleaved Ku80 still formed a Ku heterodimer and promoted DNA DSB repair activity. Taken together, these findings indicate that translocated m-calpain enhances the NHEJ pathway through the cleavage of Ku80. Based on the present study, m-calpain in DNA repair pathways might be a novel anticancer drug target, or its mechanism might be a possible route for resistance acquisition of DNA damage-inducing chemotherapeutics.
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Psychiatry (정신과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Eosu(김어수) ORCID logo https://orcid.org/0000-0001-9472-9465
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