The AMPK-TORC1 signalling axis regulates caffeine-mediated DNA damage checkpoint override and cell cycle effects in fission yeast
The AMPK-TORC1 signalling axis regulates caffeine-mediated DNA damage checkpoint override and cell cycle effects in fission yeast
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AMPK-TORC1 信号轴调节裂殖酵母中咖啡因介导的 DNA 损伤检查点覆盖和细胞周期效应
DOI：
10.1101/2022.11.08.515652
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Alao J
中科院分区：
文献类型：
--
作者：
Alao J
咖啡因是一种广泛消费的神经活性化合物，可诱导DNA损伤检查点信号覆盖，并增强对DNA损伤剂的敏感性。然而，确切的潜在机制仍然难以捉摸。在裂解酵母S.pombe中，共济失调毛细血管扩张突变(ATM)和相关共济失调毛细血管扩张突变(ATR)直系物RAD3被认为是咖啡因的细胞靶标。然而，最近的研究表明，雷帕霉素复合体1的靶点可能是主要靶点。咖啡因模拟激活Sty1调节的应激反应和AMPK同源蛋白激酶(AMPK)同源Ssp1-Ssp2通路对细胞周期进程的影响。用ATP竞争性抑制剂Torin1直接抑制TORC1，足以覆盖DNA损伤检查点信号。因此，咖啡因通过Ssp2激活间接抑制TORC1来调节细胞周期动力学是合理的。Ssp1和Ssp2的缺失抑制了咖啡因对细胞周期进程的影响。相反，直接抑制TORC1促进了这些突变体的细胞分裂。这些观察表明，咖啡因通过激活Ssp2间接抑制TORC1，从而在一定程度上推翻了DNA损伤信号。另外，Ssp1和Ssp2可能会增强咖啡因对CDC25活性的影响。AMPK-mTORC1信号轴在衰老和疾病中发挥重要作用，是化疗和放射增敏的潜在靶点。我们的结果进一步揭示了咖啡因在Sp1-AMPKTORC1Ssp2-α信号活动背景下调节细胞周期进展的潜在机制，并可能有助于开发新的饮食方案、疗法和化学增敏剂。
Caffeine, a widely consumed neuroactive compound, induces DNA damage checkpoint signalling override, and enhances sensitivity to DNA damaging agents. However, the precise underlying mechanisms have remained elusive. In fission yeast S. pombe, the Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia mutated Related (ATR) orthologue Rad3 has been proposed as the cellular target of caffeine. Nevertheless, recent studies suggest that the Target of Rapamycin Complex 1 (TORC1) might be the main target. Caffeine mimics the effects of activating the Sty1-regulated stress response and the AMP-Activated Protein Kinase (AMPK) homologue Ssp1-Ssp2 pathways on cell cycle progression. Direct inhibition of TORC1 with the ATP-competitive inhibitor torin1, is sufficient to override DNA damage checkpoint signalling. It is, therefore, plausible, that caffeine modulates cell cycle kinetics by indirectly suppressing TORC1 through Ssp2 activation. Ssp1 and ssp2 deletion suppresses the effects of caffeine on cell cycle progression. In contrast, direct inhibition of TORC1 advances cell division in these mutants. These observations suggest that caffeine overrides DNA damage signalling, in part, via the indirect inhibition of TORC1 through Ssp2 activation. Alternatively, Ssp1 and Ssp2 may potentiate the effect of caffeine on Cdc25 activity. The AMPK-mTORC1 signalling axis plays an important role in aging and disease and presents a potential target for chemo-and radio-sensitization. Our results provide further insights of the underlying mechanisms by which caffeine modulates cell cycle progression in the context of Ssp1-AMPKα Ssp2-TORC1 signalling activities and can potentially aid in the development of novel dietary regimens, therapeutics, and chemo-sensitizing agents.
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影响因子：
4.8
作者：
Bridi JC;Barros AG;Sampaio LR;Ferreira JC;Antunes Soares FA;Romano-Silva MA
通讯作者：
Romano-Silva MA
影响因子：
3.7
作者：
Calvo IA;Gabrielli N;Iglesias-Baena I;García-Santamarina S;Hoe KL;Kim DU;Sansó M;Zuin A;Pérez P;Ayté J;Hidalgo E
通讯作者：
Hidalgo E
影响因子：
2.4
作者：
Rallis C;López-Maury L;Georgescu T;Pancaldi V;Bähler J
通讯作者：
Bähler J
DOI：
10.1073/pnas.97.6.2579
发表时间：
2000-03-14
影响因子：
11.1
作者：
Christensen, PU;Bentley, NJ;Carr, AM
通讯作者：
Carr, AM
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ