Modulation of telomere protection by the PI3K/AKT pathway

Nature Communications
Marinela Méndez-PertuzMaria A Blasco

Abstract

Telomeres and the insulin/PI3K pathway are considered hallmarks of aging and cancer. Here, we describe a role for PI3K/AKT in the regulation of TRF1, an essential component of the shelterin complex. PI3K and AKT chemical inhibitors reduce TRF1 telomeric foci and lead to increased telomeric DNA damage and fragility. We identify the PI3Kα isoform as responsible for this TRF1 inhibition. TRF1 is phosphorylated at different residues by AKT and these modifications regulate TRF1 protein stability and TRF1 binding to telomeric DNA in vitro and are important for in vivo TRF1 telomere location and cell viability. Patient-derived breast cancer PDX mouse models that effectively respond to a PI3Kα specific inhibitor, BYL719, show decreased TRF1 levels and increased DNA damage. These findings functionally connect two of the major pathways for cancer and aging, telomeres and the PI3K pathway, and pinpoint PI3K and AKT as novel targets for chemical modulation of telomere protection.

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Citations

Apr 18, 2018·Current Opinion in Obstetrics & Gynecology·Carlos Balmori, Elisa Varela
Jun 21, 2018·Microcirculation : the Official Journal of the Microcirculatory Society, Inc·Yu LiuAnthony J Donato
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May 21, 2021·Oxidative Medicine and Cellular Longevity·Chao Yu, Jian-Hui Xiao

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Methods Mentioned

BETA
ubiquitination
xenograft
chromosomal aberration
sylation
electrophoretic mobility shift assay
biopsy
genotyping
PCRs

Software Mentioned

Definiens XD
Opera
Activity base
LAS
Proteome Discoverer
Fish
Sequest

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AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.