Calcium-induced cleavage of DNA topoisomerase I involves the cytoplasmic-nuclear shuttling of calpain 2 |
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Authors: | Shang-Min?Chou Ting-Hsiang?Huang Hsiang-Chin?Chen Email author" target="_blank">Tsai-Kun?LiEmail author |
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Institution: | (1) Department and Graduate Institute of Microbiology, College of Medicine, Taipei, Taiwan;(2) Center for Biotechnology, National Taiwan University, Taipei, Taiwan; |
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Abstract: | Important to the function of calpains is temporal and spatial regulation of their proteolytic activity. Here, we demonstrate
that cytoplasm-resident calpain 2 cleaves human nuclear topoisomerase I (hTOP1) via Ca2+-activated proteolysis and nucleoplasmic shuttling of proteases. This proteolysis of hTOP1 was induced by either ionomycin-caused
Ca2+ influx or addition of Ca2+ in cellular extracts. Ca2+ failed to induce hTOP1 proteolysis in calpain 2-knockdown cells. Moreover, calpain 2 cleaved hTOP1 in vitro. Furthermore,
calpain 2 entered the nucleus upon Ca2+ influx, and calpastatin interfered with this process. Calpain 2 cleavage sites were mapped at K158 and K183 of hTOP1. Calpain 2-truncated hTOP1 exhibited greater relaxation activity but remained able to interact with nucleolin and
to form cleavable complexes. Interestingly, calpain 2 appears to be involved in ionomycin-induced protection from camptothecin-induced
cytotoxicity. Thus, our data suggest that nucleocytoplasmic shuttling may serve as a novel type of regulation for calpain
2-mediated nuclear proteolysis. |
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