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GENES CELLS (2003) 8, 423-435.
Copyright © 2003 Blackwell Publishing or its licensors

Original Article

Caffeine mimics adenine and 2'-deoxyadenosine, both of which inhibit the guanine-nucleotide exchange activity of RCC1 and the kinase activity of ATR

H Nishijima, H Nishitani, N Saito, and T Nishimoto

BACKGROUND: Both caffeine and the inactivation of RCC1, the guanine-nucleotide exchange factor (GEF) of Ran, induce premature chromatin condensation (PCC) in hamster BHK21 cells arrested in the S-phase, suggesting that RCC1 is a target for caffeine. RESULTS: Caffeine inhibited the Ran-GEF activity of RCC1 by preventing the binary complex formation of Ran-RCC1. Inhibition of the Ran-GEF activity of RCC1 by caffeine and its derivatives was correlated with their ability to induce PCC. Since caffeine is a derivative of xanthine, the bases and nucleosides were screened for their ability to inhibit RCC1. Adenine, adenosine, and all of the 2'-deoxynucleosides inhibited the Ran-GEF activity of RCC1; however, only adenine and 2'-deoxyadenosine (2'-dA) induced PCC. A factor(s) other than RCC1, should therefore be involved in PCC-induction. We found that both adenine and 2'-dA, but none of the other 2'-deoxynucleosides, inhibited the kinase activity of ATR, similar to that of caffeine. The ATR pathway was also abrogated by the inactivation of RCC1 in tsBN2 cells. CONCLUSION: The effect of caffeine on cell-cycle control mimics the biological effect of adenine and 2'-dA, both of which inhibit ATR. dATP, a final metabolite of adenine and 2'-dA, is suggested to inhibit ATR, resulting in PCC.


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