p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint.
A recently identified ribonucleotide reductase (RR), p53R2, is directly regulated by p53 for supplying nucleotides to repair damaged DNA. We examined the role of this p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint, comparing it to R2-dependent DNA synthesis. The elevation of DNA synthesis activity through RR in response to gamma-irradiation was closely correlated with the level of expression of p53R2 but not of R2. The p53R2 product accumulated in nuclei, whereas R2 levels in cytoplasm decreased. We found a point mutation of p53R2 in cancer cell line HCT116, which resulted in loss of RR activity. In those cells, DNA damage-inducible apoptotic cell death was enhanced through transcriptional activation of p53AIP1. The results suggest that p53R2-dependent DNA synthesis plays a pivotal role in cell survival by repairing damaged DNA in the nucleus and that dysfunction of this pathway might result in activation of p53-dependent apoptosis to eliminate dangerous cells.
Yamaguchi
T
T
Laboratory of Molecular Medicine and Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Matsuda
K
K
Sagiya
Y
Y
Iwadate
M
M
Fujino
M A
MA
Nakamura
Y
Y
Arakawa
H
H
D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis*; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D020868:Gene Silencing; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D017354:Point Mutation; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases