Research Papers:

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 and Youngjoo Kwon _

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Oncotarget. 2016; 7:30831-30844. https://doi.org/10.18632/oncotarget.8791

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Kyung Hye Baek1, Han Vit Yu1, Eosu Kim2, Younghwa Na3, Youngjoo Kwon1

1College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea

2Department of Psychiatry, Yonsei University College of Medicine, Seoul, Republic of Korea

3College of Pharmacy, CHA University, Pocheon, Republic of Korea

Correspondence to:

Younghwa Na, email: [email protected]

Youngjoo Kwon, email: [email protected]

Keywords: m-calpain, Ku80-related DNA repair, adriamycin, DNA damage

Received: September 29, 2015     Accepted: April 01, 2016     Published: April 18, 2016


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.

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