Lars Thelander - Professor Emeritus

Regulation of deoxyribonucleotide synthesis during DNA replication and repair in eukaryotes

Background

Ribonucleotide reductase (RNR) plays a central role in the formation and control of the optimal levels of deoxyribonucleoside triphosphates, which are required for DNA replication and repair. In eukaryotic cells, both enzyme activity and the mRNAs encoding the two non-identical subunits, proteins R1 and R2, are cell cycle regulated with maximal levels during S phase.

Main objectives

1. To understand the mechanism that controls the specific proteolysis of the mouse R2 protein when cells enter mitosis. This process directly controls RNR activity during the normal cell cycle and after DNA damage in proliferating cells and may be involved in tumor transformation.
2. To elucidate the mechanisms, which regulate the transcription of the mouse RNR R1, R2 and the newly discovered p53R2 genes during the cell cycle, when quiescent cells are stimulated to proliferate and when resting cells respond to DNA damage.
3. By studying the interaction of the pure Rnr1-4 and Sml1 proteins from yeast learn how eukaryotic RNRs participate in DNA repair and replication.
4. By determining the structure of a cocrystal of the mouse RNR R1 and R2 proteins map the long-range radical transfer pathway essential for catalysis between the tyrosyl radical in the R2 protein to the active site in the R1 protein.
5. To express, purify and determine the structure of recombinant Trypanosoma brucei CTP synthetase, a putative target for the treatment of African sleeping sickness.

Publications

Author

Title

Year sorteringsordning

Fulltext

Ranjbarian, Farahnaz
Vodnala, Munender
Vodnala, Sharvani Munender; et al.

Trypanosoma brucei thymidine kinase is tandem protein consisting of two homologous parts, which together enable efficient substrate binding
Journal of Biological Chemistry, 287(21): 17628-17636

2012

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Popović-Bijelić, Ana
Voevodskaya, Nina
Domkin, Vladimir; et al.

Metal binding and activity of ribonucleotide reductase protein R2 mutants: conditions for formation of the mixed manganese-iron cofactor
Biochemistry, 48(27): 6532-6539

2009

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Pontarin, Giovanna
Fijolek, Artur
Pizzo, Paola; et al.

Ribonucleotide reduction is a cytosolic process in mammalian cells independently of DNA damage.
Proceedings of the National Academy of Sciences of the United States of America, 105(46): 17801-17806

2008

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Pontarin, Giovanna
Ferraro, Paola
Håkansson, Pelle; et al.

p53R2-dependent ribonucleotide reduction provides deoxyribonucleotides in quiescent human fibroblasts in the absence of induced DNA damage
Journal of Biological Chemistry, 282(23): 16820-8

2007

-

Thelander, Lars

Ribonucleotide reductase and mitochondrial DNA synthesis.
Nature. Genetics, 39(6): 703-4

2007

-

Fijolek, Artur
Hofer, Anders
Thelander, Lars

Expression, purification, characterization, and in vivo targeting of trypanosome CTP synthetase for treatment of African sleeping sickness.
Journal of biological chemistry, 282(16): 11858-11865

2007

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Håkansson, Pelle
Hofer, Anders
Thelander, Lars

Regulation of mammalian ribonucleotide reduction and dNTP pools after DNA damage and in resting cells.
Journal of Biological Chemistry, 281(12): 7834-7841

2006

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Håkansson, Pelle
Dahl, Lina
Chilkova, Olga; et al.

The Schizosaccharomyces pombe replication inhibitor Spd1 regulates ribonucleotide reductase activity and dNTPs by binding to the large Cdc22 subunit.
Journal of Biological Chemistry, 281(3): 1778-1783

2006

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Narváez, Ana J
Voevodskaya, Nina
Thelander, Lars; et al.

The involvement of Arg265 of mouse ribonucleotide reductase R2 protein in proton transfer and catalysis.
Journal of biological chemistry, 281(36): 26022-8

2006

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Voevodskaya, N
Narvaez, A-J
Domkin, Vladimir; et al.

Chlamydial ribonucleotide reductase: tyrosyl radical function in catalysis replaced by the FeIII-FeIV cluster.
Proceedings of the National Academy of Sciences of the United States of America, 103(26): 9850-4

2006

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Lars Thelander

Contact Information

Umeå University
Medical Biochemistry and Biophysics
SE-901 87 Umeå, SWEDEN 

Visiting Address
KBC-building, 6th floor

Tel:  +46 90 786 6742

Fax:  +46 90 786 9795

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