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Caffeine mimics adenine and 2′‐deoxyadenosine, both of which inhibit the guanine‐nucleotide exchange activity of RCC1 and the kinase activity of ATR
Author(s) -
Nishijima Hitoshi,
Nishitani Hideo,
Saito Noriko,
Nishimoto Takeharu
Publication year - 2003
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1046/j.1365-2443.2003.00644.x
Subject(s) - caffeine , biochemistry , guanine , ran , deoxyadenosine , biology , adenine nucleotide , adenosine , guanine nucleotide exchange factor , nucleotide , signal transduction , gene , endocrinology
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.