Ribonucleotide reductase subunit p53R2 regulates mitochondria homeostasis and function in KB and PC-3 cancer cells |
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Authors: | Wang Xiaochen Liu Xiyong Xue Lijun Zhang Keqiang Kuo Mei-Ling Hu Shuya Zhou Bingsen Ann David Zhang Suzhan Yen Yun |
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Affiliation: | aDepartment of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China;bDepartment of Molecular Pharmacology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, United States;cTranslational Research Core Laboratory, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, United States |
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Abstract: | Ribonucleotide reductase (RR) is a rate-limiting enzyme that catalyzes de novo conversion of ribonucleotide 5′-diphosphates to the corresponding 2′-deoxynucleotide, essential for DNA synthesis and replication. The mutations or knockout of RR small subunit, p53R2, results in the depletion of mitochondrial DNA (mtDNA) in human, implying that p53R2 might play a critical role for maintaining mitochondrial homeostasis. In this study, siRNA against p53R2 knockdown approach is utilized to examine the impact of p53R2 depletion on mitochondria and to derive underlying mechanism in KB and PC-3 cancer cells. Our results reveal that the p53R2 expression not only positively correlates with mtDNA content, but also partakes in the proper mitochondria function, such as ATP synthesis, cytochrome c oxidase activity and membrane potential maintenance. Furthermore, overexpression of p53R2 reduces intracellular ROS and protects the mitochondrial membrane potential against oxidative stress. Unexpectedly, knockdown of p53R2 has a modest, if any, effect on mitochondrial and total cellular dNTP pools. Taken together, our study provides functional evidence that mitochondria is one of p53R2-targeted organelles and suggests an unexpected function of p53R2, which is beyond known RR function on dNTP synthesis, in mitochondrial homeostatic control. |
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Keywords: | p53R2 (RRM2B) Mitochondrial DNA (mtDNA) synthesis ATP synthesis Membrane potential Cytochrome c oxidase |
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