دورية أكاديمية
Deoxyribonucleotide metabolism in cycling and resting human fibroblasts with a missense mutation in p53R2, a subunit of ribonucleotide reductase.
| العنوان: | Deoxyribonucleotide metabolism in cycling and resting human fibroblasts with a missense mutation in p53R2, a subunit of ribonucleotide reductase. |
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| المؤلفون: | Pontarin G; Department of Biology, University of Padova, Padova, Italy., Ferraro P, Rampazzo C, Kollberg G, Holme E, Reichard P, Bianchi V |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2011 Apr 01; Vol. 286 (13), pp. 11132-40. Date of Electronic Publication: 2011 Feb 05. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Mutation, Missense*, Cell Cycle/*physiology , Cell Cycle Proteins/*metabolism , DNA, Mitochondrial/*metabolism , Deoxyribonucleotides/*metabolism , Fibroblasts/*enzymology , Ribonucleotide Reductases/*metabolism, Cell Cycle Proteins/genetics ; Cells, Cultured ; DNA Repair/physiology ; DNA Replication/physiology ; DNA, Mitochondrial/genetics ; Deoxyribonucleotides/genetics ; Fibroblasts/cytology ; Humans ; Oxidation-Reduction ; Ribonucleotide Reductases/genetics ; Thymidine Kinase/genetics ; Thymidine Kinase/metabolism |
| مستخلص: | Ribonucleotide reduction provides deoxynucleotides for nuclear and mitochondrial (mt) DNA replication and DNA repair. In cycling mammalian cells the reaction is catalyzed by two proteins, R1 and R2. A third protein, p53R2, with the same function as R2, occurs in minute amounts. In quiescent cells, p53R2 replaces the absent R2. In humans, genetic inactivation of p53R2 causes early death with mtDNA depletion, especially in muscle. We found that cycling fibroblasts from a patient with a lethal mutation in p53R2 contained a normal amount of mtDNA and showed normal growth, ribonucleotide reduction, and deoxynucleoside triphosphate (dNTP) pools. However, when made quiescent by prolonged serum starvation the mutant cells strongly down-regulated ribonucleotide reduction, decreased their dCTP and dGTP pools, and virtually abolished the catabolism of dCTP in substrate cycles. mtDNA was not affected. Also, nuclear DNA synthesis and the cell cycle-regulated enzymes R2 and thymidine kinase 1 decreased strongly, but the mutant cell populations retained unexpectedly larger amounts of the two enzymes than the controls. This difference was probably due to their slightly larger fraction of S phase cells and therefore not induced by the absence of p53R2 activity. We conclude that loss of p53R2 affects ribonucleotide reduction only in resting cells and leads to a decrease of dNTP catabolism by substrate cycles that counterweigh the loss of anabolic activity. We speculate that this compensatory mechanism suffices to maintain mtDNA in fibroblasts but not in muscle cells with a larger content of mtDNA necessary for their high energy requirements. |
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| معلومات مُعتمدة: | GGP09019 Italy TI_ Telethon |
| المشرفين على المادة: | 0 (Cell Cycle Proteins) 0 (DNA, Mitochondrial) 0 (Deoxyribonucleotides) EC 1.17.4.- (RRM2B protein, human) EC 1.17.4.- (Ribonucleotide Reductases) EC 2.7.1.21 (Thymidine Kinase) EC 2.7.1.21 (thymidine kinase 1) |
| تواريخ الأحداث: | Date Created: 20110208 Date Completed: 20110601 Latest Revision: 20220129 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC3064167 |
| DOI: | 10.1074/jbc.M110.202283 |
| PMID: | 21297166 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1083-351X |
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| DOI: | 10.1074/jbc.M110.202283 |