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Lars Thelander

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.