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DBC1 phosphorylation by ATM/ATR inhibits SIRT1 deacetylase in response to DNA damage

Laura Zannini1, Giacomo Buscemi, Ja-Eun Kim

  • 1Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, I-20133 Milan, Italy.

Journal of Molecular Cell Biology
|June 28, 2012
PubMed

Insights

DNA damage triggers DBC1 phosphorylation by ATM/ATR kinases. This modification enhances DBC1

Area of Science:

  • Cellular biology
  • Molecular oncology
  • DNA damage response

Background:

  • Human DBC1 (deleted in breast cancer-1) is a nuclear protein that regulates apoptosis by inhibiting SIRT1, a key deacetylase of p53.
  • The precise mechanisms controlling DBC1's role in the DNA damage response and its interaction with SIRT1 have remained unclear.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of DBC1 in response to DNA damage.
  • To investigate the role of post-translational modifications of DBC1 in the context of genotoxic stress and apoptosis.

Main Methods:

  • Utilized human cell lines to study the effects of DNA damage on DBC1.
  • Employed kinase assays and immunoprecipitation to identify ATM and ATR as kinases phosphorylating DBC1 at Thr454.
  • Investigated the functional consequences of DBC1 phosphorylation using knockdown and phospho-mutant (DBC1(T454A)) approaches.

Main Results:

  • DNA damage induces phosphorylation of DBC1 on Thr454 by ATM and ATR kinases.
  • Phosphorylated DBC1 binds to and inhibits SIRT1, leading to dissociation of the SIRT1-p53 complex.
  • This process stimulates p53 acetylation and promotes p53-dependent apoptosis; phospho-mutant DBC1 impairs this genotoxicity.

Conclusions:

  • This study identifies the first post-translational modification of DBC1 (phosphorylation at Thr454).
  • Establishes a novel mechanistic link between ATM/ATR kinases, DBC1, SIRT1, and p53 in the DNA damage-induced apoptotic pathway.
  • Provides critical insights into the regulation of the DBC1-SIRT1-p53 axis in response to genotoxic stress.

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