Modulation of telomere protection by the PI3K/AKT pathway

Marinela Méndez-Pertuz, Paula Martínez, Carmen Blanco-Aparicio, Elena Gómez-Casero, Ana Belen García, Jorge Martínez-Torrecuadrada, Marta Palafox, Javier Cortés, Violeta Serra, Joaquin Pastor and Maria A. Blasco ()
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Marinela Méndez-Pertuz: Molecular Oncology Program, Spanish National Cancer Centre (CNIO)
Paula Martínez: Molecular Oncology Program, Spanish National Cancer Centre (CNIO)
Carmen Blanco-Aparicio: Spanish National Cancer Centre (CNIO)
Elena Gómez-Casero: Spanish National Cancer Centre (CNIO)
Ana Belen García: Spanish National Cancer Centre (CNIO)
Jorge Martínez-Torrecuadrada: Spanish National Cancer Centre (CNIO)
Marta Palafox: Vall d´Hebron Institute of Oncology (VHIO)
Javier Cortés: Vall d´Hebron Institute of Oncology (VHIO)
Violeta Serra: Vall d´Hebron Institute of Oncology (VHIO)
Joaquin Pastor: Spanish National Cancer Centre (CNIO)
Maria A. Blasco: Molecular Oncology Program, Spanish National Cancer Centre (CNIO)

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01329-2

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