title: Ribonucleotide reductase subunit p53R2 regulates mitochondria homeostasis and function in KB and PC-3 cancer cells.
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.
authors.affiliation: Department of Surgical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Wang
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.forename: Lijun
authors.initials: L
authors.lastname: Xue
authors.forename: Keqiang
authors.initials: K
authors.lastname: Zhang
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Kuo
authors.forename: Shuya
authors.initials: S
authors.lastname: Hu
authors.forename: Bingsen
authors.initials: B
authors.lastname: Zhou
authors.forename: David
authors.initials: D
authors.lastname: Ann
authors.forename: Suzhan
authors.initials: S
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000201:enzymology*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004272:DNA, Mitochondrial; D000255:Adenosine Triphosphate; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; D003576:Electron Transport Complex IV