Akt regulates TPP1 homodimerization and telomere protection

Aging Cell. 2013 Dec;12(6):1091-9. doi: 10.1111/acel.12137. Epub 2013 Aug 11.

Abstract

Telomeres are specialized structures at the ends of eukaryotic chromosomes that are important for maintaining genome stability and integrity. Telomere dysfunction has been linked to aging and cancer development. In mammalian cells, extensive studies have been carried out to illustrate how core telomeric proteins assemble on telomeres to recruit the telomerase and additional factors for telomere maintenance and protection. In comparison, how changes in growth signaling pathways impact telomeres and telomere-binding proteins remains largely unexplored. The phosphatidylinositol 3-kinase (PI3-K)/Akt (also known as PKB) pathway, one of the best characterized growth signaling cascades, regulates a variety of cellular function including cell proliferation, survival, metabolism, and DNA repair, and dysregulation of PI3-K/Akt signaling has been linked to aging and diseases such as cancer and diabetes. In this study, we provide evidence that the Akt signaling pathway plays an important role in telomere protection. Akt inhibition either by chemical inhibitors or small interfering RNAs induced telomere dysfunction. Furthermore, we found that TPP1 could homodimerize through its OB-fold, a process that was dependent on the Akt kinase. Telomere damage and reduced TPP1 dimerization as a result of Akt inhibition was also accompanied by diminished recruitment of TPP1 and POT1 to the telomeres. Our findings highlight a previously unknown link between Akt signaling and telomere protection.

Keywords: Akt; TPP1; telomere protection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopeptidases / chemistry
  • Aminopeptidases / metabolism*
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / chemistry
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism*
  • Humans
  • Isoenzymes / metabolism
  • Protein Multimerization*
  • Protein Structure, Secondary
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Serine Proteases / chemistry
  • Serine Proteases / metabolism*
  • Telomere / metabolism*
  • Telomere-Binding Proteins / metabolism

Substances

  • Isoenzymes
  • POT1 protein, human
  • Telomere-Binding Proteins
  • Proto-Oncogene Proteins c-akt
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • tripeptidyl-peptidase 1