A Divergent Role of the SIRT1-TopBP1 Axis in Regulating Metabolic Checkpoint and DNA Damage Checkpoint

Tongzheng Liu, Yi Hui Lin, Wenchuan Leng, SungYun Jung, Haoxing Zhang, Min Deng, Debra Evans, Yunhui Li, Kuntian Luo, Bo Qin, Jun Qin, Jian Yuan, Zhenkun Lou

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25 Scopus citations

Abstract

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 that the SIRT1-TopBP1 axis functions as a switch for both checkpoints. With 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, weshowed 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 the SIRT1-TopBP1 axis as a key signaling mode in the regulation of the metabolic checkpoint and the DNA damage checkpoint.

Original languageEnglish (US)
Pages (from-to)681-695
Number of pages15
JournalMolecular Cell
Volume56
Issue number5
DOIs
StatePublished - Dec 4 2014

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Medicine(all)

Cite this

Liu, T., Lin, Y. H., Leng, W., Jung, S., Zhang, H., Deng, M., Evans, D., Li, Y., Luo, K., Qin, B., Qin, J., Yuan, J., & Lou, Z. (2014). A Divergent Role of the SIRT1-TopBP1 Axis in Regulating Metabolic Checkpoint and DNA Damage Checkpoint. Molecular Cell, 56(5), 681-695. https://doi.org/10.1016/j.molcel.2014.10.007