AKT-dependent signaling of extracellular cues through telomeres impact on tumorigenesis

PLoS Genet. 2021 Mar 9;17(3):e1009410. doi: 10.1371/journal.pgen.1009410. eCollection 2021 Mar.

Abstract

The telomere-bound shelterin complex is essential for chromosome-end protection and genomic stability. Little is known on the regulation of shelterin components by extracellular signals including developmental and environmental cues. Here, we show that human TRF1 is subjected to AKT-dependent regulation. To study the importance of this modification in vivo, we generate knock-in human cell lines carrying non-phosphorylatable mutants of the AKT-dependent TRF1 phosphorylation sites by CRISPR-Cas9. We find that TRF1 mutant cells show decreased TRF1 binding to telomeres and increased global and telomeric DNA damage. Human cells carrying non-phosphorylatable mutant TRF1 alleles show accelerated telomere shortening, demonstrating that AKT-dependent TRF1 phosphorylation regulates telomere maintenance in vivo. TRF1 mutant cells show an impaired response to proliferative extracellular signals as well as a decreased tumorigenesis potential. These findings indicate that telomere protection and telomere length can be regulated by extracellular signals upstream of PI3K/AKT activation, such as growth factors, nutrients or immune regulators, and this has an impact on tumorigenesis potential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism*
  • DNA Damage
  • Genomic Instability
  • Humans
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction*
  • Telomere / genetics*
  • Telomere / metabolism*
  • Telomere Shortening
  • Telomeric Repeat Binding Protein 1 / genetics
  • Telomeric Repeat Binding Protein 1 / metabolism

Substances

  • Telomeric Repeat Binding Protein 1
  • Proto-Oncogene Proteins c-akt
  • Proteasome Endopeptidase Complex

Grant support

Research in the Blasco lab is funded by Spanish State Research Agency (AEI), Ministry of Science and Innovation (SAF2017-82623-R (PM and MAB)and SAF2015-72455-EXP (MAB)), the Comunidad de Madrid Project (S2017/BMD-3770)(MAB), the World Cancer Research (WCR) Project (16-1177) (MAB), the European Research Council (ERC-AvG Shelterines GA882385) (MAB) and the Fundación Botín (Spain) (MAB). R.S-V is a recipient of a doctoral scholarship from CONACYT-México. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.