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[Cancer Research 61, 8256-8262, November 15, 2001]
© 2001 American Association for Cancer Research

Molecular Biology and Genetics

p53R2-dependent Pathway for DNA Synthesis in a p53-regulated Cell Cycle Checkpoint1

Tatsuya Yamaguchi, Koichi Matsuda, Yoji Sagiya, Manabu Iwadate, Masayuki A. Fujino, Yusuke Nakamura2 and Hirofumi Arakawa

Laboratory of Molecular Medicine and Genome Technology, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639 [T. Y., K. M., Y. S., M. I., Y. N., H. A.], and First Department of Medicine, Yamanashi Medical University School of Medicine, Yamanashi 409-3898 [T. Y., M. A. F.], Japan

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.




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Copyright © 2001 by the American Association for Cancer Research.