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Ribonucleotide reductase and DNA damage
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A prerequisite for a multicellular organism to survive is the ability to correctly replicate and repair DNA while minimizing the number of heritable mutations. To achieve this, cells need a balanced supply of deoxyribonucleoside triphosphates (dNTPs), the precursors for DNA synthesis. The rate-limiting step in de novo biosynthesis of dNTPs is catalyzed by the enzyme ribonucleotide reductase (RNR).

The classic eukaryotic RNR enzyme consists of a large and a small subunit. Together, these subunits form a heterotetrameric RNR complex. The larger subunit harbours active sites whereas the smaller subunit contains a stable tyrosyl free radical. Both subunits are required for RNR activity.

Since failure to correctly regulate de novo dNTP biosynthesis can lead to misincorporation of nucleotides into DNA, genetic abnormalities and cell death, RNR activity is tightly regulated. The regulation of RNR activity involves cell cycle-specific expression and degradation of the RNR proteins, as well as binding of allosteric effectors to the large RNR subunit.

In this thesis, in vitro assays based on purified recombinant RNR proteins, in combination with in vivo assays, have been used successfully to study the regulation of RNR activity in response to DNA damage. I present new findings regarding the function of an alternative mammalian RNR small subunit, and on the role of a small RNR inhibitor protein of fission yeast, during normal growth and after DNA damage. I also show conclusively that there are fundamental differences in the regulation of dNTP biosynthesis between the cells of higher and lower eukaryotes after DNA damage.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2006. , 48 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1008
Keyword [en]
ribonucleotide reductase, DNA damage, dNTP pools
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-706ISBN: 91-7264-009-X (print)OAI: oai:DiVA.org:umu-706DiVA: diva2:144271
Public defence
2006-03-17, KB3A9, KBC, Umeå Universitet, 90187 Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-02-23 Created: 2006-02-23 Last updated: 2012-03-22Bibliographically approved
List of papers
1. Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro with the R1 protein, which is expressed both in resting cells in response to DNA damage and in proliferating cells
Open this publication in new window or tab >>Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro with the R1 protein, which is expressed both in resting cells in response to DNA damage and in proliferating cells
Show others...
2001 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 276, no 44, 40647-40651 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-4954 (URN)10.1074/jbc.M106088200 (DOI)11517226 (PubMedID)
Available from: 2006-02-23 Created: 2006-02-23 Last updated: 2017-12-14Bibliographically approved
2. Regulation of mammalian ribonucleotide reduction and dNTP pools after DNA damage and in resting cells.
Open this publication in new window or tab >>Regulation of mammalian ribonucleotide reduction and dNTP pools after DNA damage and in resting cells.
2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 12, 7834-7841 p.Article in journal (Refereed) Published
Keyword
Animals, Catalysis, Cell Cycle, DNA/chemistry/metabolism, DNA Damage, DNA Repair, DNA Replication, DNA; Mitochondrial/metabolism, Deoxyribonucleotides/*chemistry, Dose-Response Relationship; Drug, Fibroblasts/metabolism, Flow Cytometry, Free Radicals, G0 Phase, G1 Phase, Hydroxyurea/chemistry, Immunoblotting, Mice, Mice; Inbred BALB C, Mitochondria/metabolism, NIH 3T3 Cells, Protein Binding, Recombinant Proteins/chemistry, Ribonucleotide Reductases/chemistry, Ribonucleotides/*chemistry, S Phase, Saccharomycetales, Time Factors, Up-Regulation
Identifiers
urn:nbn:se:umu:diva-6343 (URN)10.1074/jbc.M512894200 (DOI)16436374 (PubMedID)
Available from: 2007-12-09 Created: 2007-12-09 Last updated: 2017-12-14Bibliographically approved
3. The Schizosaccharomyces pombe replication inhibitor Spd1 regulates ribonucleotide reductase activity and dNTPs by binding to the large Cdc22 subunit.
Open this publication in new window or tab >>The Schizosaccharomyces pombe replication inhibitor Spd1 regulates ribonucleotide reductase activity and dNTPs by binding to the large Cdc22 subunit.
Show others...
2006 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, no 3, 1778-1783 p.Article in journal (Refereed) Published
Keyword
Cell Cycle Proteins/genetics/*metabolism/*physiology, Cloning; Molecular, DNA Replication, Deoxyribonucleotides/*metabolism, Escherichia coli/genetics, G1 Phase, Kinetics, Protein Subunits/metabolism, Recombinant Proteins/isolation & purification/metabolism, Ribonucleotide Reductases/antagonists & inhibitors/genetics/*metabolism, Schizosaccharomyces/cytology/enzymology/*genetics, Schizosaccharomyces pombe Proteins/genetics/*metabolism/*physiology
Identifiers
urn:nbn:se:umu:diva-6344 (URN)10.1074/jbc.M511716200 (DOI)16317005 (PubMedID)
Available from: 2007-12-09 Created: 2007-12-09 Last updated: 2017-12-14Bibliographically approved

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