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Enzyme Kinetics of the Mitochondrial Deoxyribonucleoside Salvage Pathway Are Not Sufficient to Support Rapid mtDNA Replication

Vishal V. Gandhi, David C. Samuels, Ruth Nussinov
2011 PLoS Computational Biology  
Our analysis of the enzyme kinetics also revealed that the majority of enzymes of this pathway prefer substrates that are not precursors (canonical deoxyribonucleosides and deoxyribonucleotides) for mitochondrial  ...  Our results indicate that the output from the mitochondrial salvage enzymes alone is inadequate to support a mitochondrial DNA replication duration of as long as 10 hours.  ...  Summary Since the known elements of the mitochondrial salvage pathway do not have sufficient enzyme kinetics to support mtDNA replication in the observed duration of ,1-2 hours, then, an alternative source  ... 
doi:10.1371/journal.pcbi.1002078 pmid:21829339 pmcid:PMC3150320 fatcat:mzskscrrxbcz3iuzehj6fd426e

DNA precursor metabolism and genomic stability

Christopher K. Mathews
2006 The FASEB Journal  
Intracellular concentrations of the four deoxyribonucleoside triphosphates (dNTPs) are closely regulated, and imbalances in the four dNTP pools have genotoxic consequences.  ...  Replication errors leading to mutations can occur, for example, if one dNTP in excess drives formation of a non-Watson-Crick base pair or if it forces replicative DNA chain elongation past a mismatch before  ...  Figure 1 . 1 Pathways of de novo dNTP synthesis in mammalian cells. Salvage pathways are not shown. Each enzyme name is in italics.  ... 
doi:10.1096/fj.06-5730rev pmid:16816105 fatcat:i55m7d5cvfhalpvtgszumncgn4

Measurement of mitochondrial DNA synthesis in vivo using a stable isotope-mass spectrometric technique

Michelle L. Collins, Shannon Eng, Rebeccah Hoh, Marc K. Hellerstein
2003 Journal of applied physiology  
In conclusion, replication of mtDNA can be directly measured in vivo in rodents and humans without the use of radioactivity.  ...  Mitochondria were isolated from cardiac and hindlimb muscle, and mtDNA was isolated and enzymatically hydrolyzed to deoxyribonucleosides. PCR confirmed the absence of nuclear DNA contamination.  ...  Also, we are grateful to Dr. Barry Shane for use of the Taq-Man instrument.  ... 
doi:10.1152/japplphysiol.00691.2002 pmid:12562673 fatcat:jnt2hzcu7vewteeic22bpot67q

Origins of mitochondrial thymidine triphosphate: Dynamic relations to cytosolic pools

G. Pontarin, L. Gallinaro, P. Ferraro, P. Reichard, V. Bianchi
2003 Proceedings of the National Academy of Sciences of the United States of America  
The rapid mixing of the cytosolic and mt pools was not expected from earlier data.  ...  We propose that in proliferating cells dNTPs for mtDNA come largely from import of cytosolic nucleotides, whereas intra-mt salvage of deoxyribonucleosides provides dNTPs in resting cells.  ...  Several genetic diseases affecting mtDNA replication arise from malfunction of enzymes in either mt pathway (14, 15) .  ... 
doi:10.1073/pnas.1635259100 pmid:14519855 pmcid:PMC218729 fatcat:6cbhegtt6nhh5kk64kvztamkzq

Mitochondrial Thymidine Kinase and the Enzymatic Network Regulating Thymidine Triphosphate Pools in Cultured Human Cells

Chiara Rampazzo, Sonia Fabris, Elisa Franzolin, Katia Crovatto, Miriam Frangini, Vera Bianchi
2007 Journal of Biological Chemistry  
In the former pool dNTPs are produced from ribonucleotides by the de novo pathway, where ribonucleotide reductase and thymidylate synthase are key enzymes, and by phosphorylation of deoxyribonucleosides  ...  via the salvage pathway. mt dNTPs derive from the salvage of deoxyribonucleosides catalyzed by mt kinases and from import of deoxyribonucleotides preformed in the cytosol.  ...  In the former pool dNTPs are produced from ribonucleotides by the de novo pathway, where ribonucleotide reductase and thymidylate synthase are key enzymes, and by phosphorylation of deoxyribonucleosides  ... 
doi:10.1074/jbc.m705923200 pmid:17913703 fatcat:y6vhwqsq7famnhrppnlg5r62aq

Deoxynucleoside Salvage Facilitates DNA Repair During Ribonucleotide Reductase Blockade in Human Cervical Cancers

Charles A. Kunos, Gina Ferris, Natalie Pyatka, John Pink, Tomas Radivoyevitch
2011 Radiation Research  
Cells generate 2′-deoxyribonucleoside triphosphates (dNTPs) for both replication and repair of damaged DNA predominantly through de novo reduction of intracellular ribonucleotides by ribonucleotide reductase  ...  (3-AP, NSC no. 663249) impairs the de novo pathway.  ...  Acknowledgments This research was supported in part by NIH grant P30 CA43703 and the Clinical & Translational Science Collaborative for use of the Translational Research Core Facility, the Radiation Core  ... 
doi:10.1667/rr2556.1 pmid:21756082 pmcid:PMC3191339 fatcat:ojzq6krpx5acpcoyxnm7bjzsne

Strategies for fighting mitochondrial diseases

Carlo Viscomi, Massimo Zeviani
2020 Journal of Internal Medicine  
and regulation, components of the mtDNA replication and expression machinery, biosynthetic enzymes for the biosynthesis or incorporation of prosthetic groups, components of the mitochondrial quality control  ...  tangible results for the development of strategies amenable to the treatment of patients with these tremendously difficult conditions are not so far away.  ...  Acknowledgements Prof Jan Smeitink for critically reading the manuscript. Conflict of interest statement No conflicts of interest to declare.  ... 
doi:10.1111/joim.13046 pmid:32100338 fatcat:kivbvap4sng7zhdyhzljcfs66m

Ribonucleotide reductase and cancer: biological mechanisms and targeted therapies

Y Aye, M Li, M J C Long, R S Weiss
2014 Oncogene  
A key requirement for the maintenance of genomic integrity is the availability of adequate and balanced pools of deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA.  ...  Notably, dNTP pool alterations lead to genomic instability and have been linked to multiple human diseases, including mitochondrial disorders, susceptibility to viral infection and cancer.  ...  YA acknowledges a faculty development grant from the ACCEL program supported by NSF (SBE-0547373), an Affinito-Stewart grant from the President's Council of Cornell Women and a Milstein sesquicentennial  ... 
doi:10.1038/onc.2014.155 pmid:24909171 fatcat:kms7qb3prfetle3ae7xdpannue

p53R2-dependent Ribonucleotide Reduction Provides Deoxyribonucleotides in Quiescent Human Fibroblasts in the Absence of Induced DNA Damage

Giovanna Pontarin, Paola Ferraro, Pelle Håkansson, Lars Thelander, Peter Reichard, Vera Bianchi
2007 Journal of Biological Chemistry  
We suggest that in quiescent cells an important function of p53R2 is to provide deoxynucleotides for mitochondrial DNA replication. . 2 The abbreviations used are: mt, mitochondrial; FCS, fetal calf serum  ...  In cycling cells the de novo pathway dominates, but in quiescent cells the salvage pathway becomes important. Two forms of active mammalian ribonucleotide reductases are known.  ...  In cultured cells kinetic experiments with labeled thymidine supported the existence of the two pathways for the synthesis of mt dNTPs and the predominance of the salvage pathway in quiescent cells (13  ... 
doi:10.1074/jbc.m701310200 pmid:17416930 fatcat:i75kwgpyvndh3czpf55z2z2vbe

SAMHD1 limits the efficacy of forodesine in leukaemia by protecting cells against cytotoxicity of dGTP [article]

Tamara Davenne, Jenny Klintman, Sushma Sharma, Rachel E Rigby, Chiara Cursi, Anne Bridgeman, Bernadeta Dadonaite, Kim De Keersmaecker, Peter Hillmen, Andrei Chabes, Anna Schuh, Jan Rehwinkel
2020 bioRxiv   pre-print
We report that SAMHD1, a phosphohydrolase degrading deoxyribonucleoside triphosphates (dNTPs), protected cells against the effects of dNTP imbalances.  ...  The anti-leukaemia agent forodesine causes cytotoxic overload of intracellular deoxyguanosine triphosphate (dGTP) but is efficacious only in a subset of patients.  ...  The salvage pathway involves uptake of 67 deoxyribonucleosides (dNs) from the extracellular environment, followed by 68 intracellular phosphorylation by cytosolic and mitochondrial kinases to form dNTPs  ... 
doi:10.1101/2020.02.17.951517 fatcat:h3gzlggh75bubmfmobcxfkqd4u

Mitochondrial Import [chapter]

2008 Encyclopedia of Genetics, Genomics, Proteomics and Informatics  
The unfused myeloma cells are also eliminated on a HAT medium because they cannot synthesize nucleic acids, either by the de novo or by the salvage pathway.  ...  Therefore, careful collection of data, replications, sufficient sample sizes, etc., are indispensable for accuracy and predictability.  ...  Mitochondria depend, either on the salvage pathway for deoxyribonucleotides or on special transporters to provide these DNA precursors. Human mitochondria have only two deoxyribonucleoside kinases.  ... 
doi:10.1007/978-1-4020-6754-9_10535 fatcat:kablmiledvdx3lxxk4j3tsicca

MITE (mariner insect transposon-like element, miniature inverted-repeat transposable element) [chapter]

2008 Encyclopedia of Genetics, Genomics, Proteomics and Informatics  
The unfused myeloma cells are also eliminated on a HAT medium because they cannot synthesize nucleic acids, either by the de novo or by the salvage pathway.  ...  Therefore, careful collection of data, replications, sufficient sample sizes, etc., are indispensable for accuracy and predictability.  ...  Mitochondria depend, either on the salvage pathway for deoxyribonucleotides or on special transporters to provide these DNA precursors. Human mitochondria have only two deoxyribonucleoside kinases.  ... 
doi:10.1007/978-1-4020-6754-9_10520 fatcat:tj67vdv34vc63hlfupk6xahu24

International meeting on "Molecular biology of DNA repair." Presented by the British Photobiology Society and DNA Repair Information Network. 16-18 April, 1986, Manchester. Abstracts of posters

1986 British Journal of Cancer  
Analysis of the enzyme activities of SA236 showed that certain enzymes of DNA repair pathways, noticeably DNA polymerase I, are synthesised in higher concentrations by the cell.  ...  the synthesis of this enzyme is repressed.  ...  We have used radioimmunoassay to measure the preferential formation of 06-methylguanine (O6-MeG) in rat hepatic mitochondrial DNA (mtDNA) compared to nuclear DNA (nDNA).  ... 
pmid:3741771 pmcid:PMC2001529 fatcat:ixd227zbmneaxlp2cf3hs2f57u

International meeting on "Molecular biology of DNA repair." Presented by the British Photobiology Society and DNA Repair Information Network. 16-18 April, 1986, Manchester. Abstracts of posters

1986 British Journal of Cancer  
Analysis of the enzyme activities of SA236 showed that certain enzymes of DNA repair pathways, noticeably DNA polymerase I, are synthesised in higher concentrations by the cell.  ...  the synthesis of this enzyme is repressed.  ...  We have used radioimmunoassay to measure the preferential formation of 06-methylguanine (O6-MeG) in rat hepatic mitochondrial DNA (mtDNA) compared to nuclear DNA (nDNA).  ... 
doi:10.1038/bjc.1986.184 fatcat:oc7br652pvcefbiwgsapu4uwku

On the Regulation of Mitochondrial Fusion, Fission and Mitochondrial DNA [article]

Rasha Sabouny, University Of Calgary, Timothy E. Shutt
2020
Dynamic fusion and fission forces are also key for distributing mtDNA nucleoids throughout mitochondrial networks and the maintenance of mtDNA copy number.  ...  However, we do not completely understand how or why these processes are important for mtDNA.  ...  SLC25A4, AGK and MPV17) or the activity of proteins in the mitochondrial salvage pathway (e.g. TK2, DGUOK, SUCLG1, SUCLA2, and ABAT).  ... 
doi:10.11575/prism/37680 fatcat:xfw4b76dsngbdc2p4s47yj7yai