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

Author summary We show how extracellular milieu information is transmitted to the nucleus through modifications in the telomeric protein TRF1. TRF1, a component of the shelterin complex that protects the ends of our chromosomes, is modified by the PI3K/AKT signaling pathway, which senses the extracellular nutritional conditions. We generated knock-in human cell lines carrying mutant TRF1 variants unable to be modified by AKT. TRF1 mutant cells show decreased TRF1 binding to telomeres, increased DNA damage and accelerated telomere shortening. TRF1 mutant cells show an impaired TRF1 stability in response to proliferative extracellular signals and a decreased tumorigenesis potential, demonstrating that telomere function and telomere length are regulated by extracellular signals upstream of PI3K/AKT activation. 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.

Automated summary

This study demonstrates how extracellular signals can regulate telomere protection and length through modifications in TRF1 protein. Mutations in TRF1 lead to decreased telomere binding, increased DNA damage, accelerated telomere shortening, impaired response to proliferative signals, and decreased tumorigenesis potential. It highlights the role of PI3K/AKT pathway in regulating telomere maintenance and suggests potential targets for cancer therapy.