Mimosine induces p27Kip1 expression via transcriptional activation

Abstract

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 DNA repair processes. Mammalian RNRs are composed of two nonidentical subunits, proteins R1 and R2. The levels of the limiting R2 protein control overall RNR activity during the cell cycle, being undetectable in G1 phase and increasing in S phase. We show that in proliferating mammalian cells, the transcription of the R2 gene, once activated in the beginning of S phase, reaches its maximum 6-7 hours later and then declines. Interestingly, DNA damage and replication blocks, which arrest the cell cycle, neither increase nor prolong the R2 promoter activity in S phase; consequently, the R2 promoter activity is uncoupled from the S phase progression. Contrary to the existing transcriptional model, we demonstrate that the cell cycle activity of the mammalian RNR is controlled by an S-phase specific stabilization of the R2 protein, which is effective until cells pass into mitosis, when the protein is rapidly degraded.1308 Mimosine induces p27Kipl expression via transcriptional activation