Inositol Pyrophosphates Mediate the DNA-PK/ATM-p53 Cell Death Pathway by Regulating CK2 Phosphorylation of Tti1/Tel2

Feng Rao, Jiyoung Cha, Jing Xu, Risheng Xu, M. Scott Vandiver, Richa Tyagi, Robert Tokhunts, Michael A. Koldobskiy, Chenglai Fu, Roxanne Barrow, Mingxuan Wu, Dorothea Fiedler, James C. Barrow, Solomon H. Snyder

Research output: Contribution to journalArticlepeer-review

Abstract

The apoptotic actions of p53 require its phosphorylation by a family of phosphoinositide-3-kinase-related-kinases (PIKKs), which include DNA-PKcs and ATM. These kinases are stabilized by the TTT (Tel2, Tti1, Tti2) cochaperone family, whose actions are mediated by CK2 phosphorylation. The inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks), of which IP6K2 has been implicated in p53-associated cell death. In the present study we report an apoptotic signaling cascade linking CK2, TTT, the PIKKs, and p53. We demonstrate that IP7, formed by IP6K2, binds CK2 to enhance its phosphorylation of the TTT complex, thereby stabilizing DNA-PKcs and ATM. This process stimulates p53 phosphorylation at serine 15 to activate the cell death program in human cancer cells and in murine B cells.

Original languageEnglish (US)
Pages (from-to)119-132
Number of pages14
JournalMolecular cell
Volume54
Issue number1
DOIs
StatePublished - Apr 10 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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