A divergent role of the SIRT1-TopBP1 axis in regulating metabolic checkpoint and DNA damage checkpoint.
A divergent role of the SIRT1-TopBP1 axis in regulating metabolic checkpoint and DNA damage checkpoint.
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DOI：
10.1016/j.molcel.2014.10.007
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发表时间：
2014-12-04
期刊：
影响因子：
16
通讯作者：
Lou Z
中科院分区：
文献类型：
--
作者：
Liu T;Lin YH;Leng W;Jung SY;Zhang H;Deng M;Evans D;Li Y;Luo K;Qin B;Qin J;Yuan J;Lou Z
DNA replication is executed only when cells have sufficient metabolic resources and undamaged DNA. Nutrient limitation and DNA damage cause a metabolic checkpoint and DNA damage checkpoint, respectively. Although SIRT1 activity is regulated by metabolic stress and DNA damage, its function in these stress-mediated checkpoints remains elusive. Here we report the SIRT1-TopBP1 axis functions as a switch for both checkpoints. Under glucose deprivation, SIRT1 is activated and deacetylates TopBP1, resulting in TopBP1-Treslin disassociation and DNA replication inhibition. Conversely, SIRT1 activity is inhibited under genotoxic stress, resulting in increased TopBP1 acetylation that is important for the TopBP1-Rad9 interaction and activation of the ATR-Chk1 pathway. Mechanistically, we showed that acetylation of TopBP1 changes the conformation of TopBP1, thereby facilitating its interaction with distinct partners in DNA replication and checkpoint activation. Taken together, our studies identify SIRT1-TopBP1 axis as a key signaling mode in the regulation of metabolic checkpoint and DNA damage checkpoint.
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DOI：
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发表时间：
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期刊：
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影响因子：
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