Abstract
The widely consumed neuroactive compound caffeine has generated much interest due to its ability to override the DNA damage and replication checkpoints. Previously Rad3 and its homologues was thought to be the target of caffeine’s inhibitory activity. Later findings indicate that the Target of Rapamycin Complex 1 (TORC1) is the preferred target of caffeine. Effective Cdc2 inhibition requires both the activation of the Wee1 kinase and inhibition of the Cdc25 phosphatase. The TORC1, DNA damage, and environmental stress response pathways all converge on Cdc25 and Wee1. We previously demonstrated that caffeine overrides DNA damage checkpoints by modulating Cdc25 stability. The effect of caffeine on cell cycle progression resembles that of TORC1 inhibition. Furthermore, caffeine activates the Sty1 regulated environmental stress response. Caffeine may thus modulate multiple signalling pathways that regulate Cdc25 and Wee1 levels, localisation and activity. Here we show that the activity of caffeine stabilises both Cdc25 and Wee1. The stabilising effect of caffeine and genotoxic agents on Wee1 was dependent on the Rad24 chaperone. Interestingly, caffeine inhibited the accumulation of Wee1 in response to DNA damage. Caffeine may modulate cell cycle progression through increased Cdc25 activity and Wee1 repression following DNA damage via TORC1 inhibition, as TORC1 inhibition increased DNA damage sensitivity.
Highlights
Cell cycle progression through mitosis is under the opposing control of the Cdc25 phosphatase and the Wee1 kinase
Caffeine stabilised Wee1 in a Rad24 dependent manner under normal cell cycle conditions. These findings demonstrate that caffeine overrides the DNA damage checkpoints by positively regulating Cdc25 and negatively regulating Wee1
As caffeine inhibits Target of Rapamycin Complex 1 (TORC1) and advances entry into mitosis [16,18], we investigated if TORC1 inhibition overrides checkpoint signalling
Summary
Cell cycle progression through mitosis is under the opposing control of the Cdc phosphatase and the Wee kinase. DNA damage activates the Ataxia and Telangiectasia Mutated (ATM) homologue Rad which in turn, activates the downstream checkpoint kinases Cds and Chk in the S- and G2- cell cycle phases respectively (Alao and Sunnerhagen, 2008). Deletion of the rad3+ gene and its downstream target Cds resulted in Cdc stabilisation These findings suggested a role of Rad signalling in regulating Cdc stability during the normal cell cycle. Caffeine stabilised Wee in a Rad dependent manner under normal cell cycle conditions These findings demonstrate that caffeine overrides the DNA damage checkpoints by positively regulating Cdc and negatively regulating Wee. These findings demonstrate that caffeine overrides the DNA damage checkpoints by positively regulating Cdc and negatively regulating Wee1 They provide further evidence for the assertion that caffeine modulates TORC1 (and other pathways) and not Rad signalling to overcome the DNA damage checkpoint “double lock” mechanism
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