Mice with reduced expression of the telomere‐associated protein Ft1 develop p53‐sensitive progeroid traits

Abstract

SummaryHuman AKTIP and mouse Ft1 are orthologous ubiquitin E2 variant proteins involved in telomere maintenance and DNA replication. AKTIP also interacts with A‐ and B‐type lamins. These features suggest that Ft1 may be implicated in aging regulatory pathways. Here, we show that cells derived from hypomorph Ft1 mutant (Ft1 kof/kof) mice exhibit telomeric defects and that Ft1 kof/kof animals develop progeroid traits, including impaired growth, skeletal and skin defects, abnormal heart tissue, and sterility. We also demonstrate a genetic interaction between Ft1 and p53. The analysis of mice carrying mutations in both Ft1 and p53 (Ft1 kof/kof ; p53 ko/ko and Ft1 kof/kof ; p53 +/ko) showed that reduction in p53 rescues the progeroid traits of Ft1 mutants, suggesting that they are at least in part caused by a p53‐dependent DNA damage response. Conversely, Ft1 reduction alters lymphomagenesis in p53 mutant mice. These results identify Ft1 as a new player in the aging process and open the way to the analysis of its interactions with other progeria genes using the mouse model.

Genomic instability and DNA replication defects in progeroid syndromes

“…We described that AKTIP dysfunction causes DNA replication and telomere defects, which in turn generate DNA damage activation and cell senescence [63]. Consistently with the connection of AKTIP both with lamins and DNA function, hypomorphic mice (Ft1 kof/kof , Ft1 Knock out first) displayed premature aging defects, including reduced body size, lipodistrophy, altered bone density and kyphosis [64]. We demonstrated that the phenotype is partly rescued by co-depletion of p53, pointing to the interplay between DNA damage and progeria.…”

“…We observed progeroid traits in a mouse model defective in a gene implicated in DNA function named AKTIP (in humans and Ft1 in mouse) [63][64][65]. We described that AKTIP dysfunction causes DNA replication and telomere defects, which in turn generate DNA damage activation and cell senescence [63].…”

Human AKTIP interacts with ESCRT proteins and functions at the midbody in cytokinesis

“…A reduction in AKTIP expression resulted in multiple telomeric signals coupled with the activation of DNA damage markers and with the disorganization of chromatin. In mice, Ft1 reduction causes premature aging defects that are partially rescued by reducing the expression of the DNA damage sensor p53 (15, 16). AKTIP is distributed in the nucleus in a punctate pattern and decorates the nuclear rim in interphase (12, 17).…”

p53-Sensitive Epileptic Behavior and Inflammation in Ft1 Hypomorphic Mice

“…Understanding the mechanistic path to disease is complex in humans due to ethical issues, unavailability of controls and high costs of human research. As a result, studies mostly rely on the use of models, including human 3D cultures and stem cell based systems (Riminucci et al, 2006 ; Simão et al, 2015 ), or, for organismal analyses, genetically engineered mice (Baraban, 2007 ; Saggio et al, 2014 ; Remoli et al, 2015 ; La Torre et al, 2018 ). One of the way in which epilepsy has been modeled in mice is via the inactivation of genes implicated in ion channels (Yu et al, 2006 ; Baraban, 2007 ; Glasscock et al, 2012 ), or of genes encoding for neurotransmitter receptors (Fonck et al, 2005 ).…”

“…AKTIP/Ft1 reduction causes telomere aberrations, DNA instability and cell senescence (Burla et al, 2015 ). In vivo , the genetic reduction of Ft1 causes premature aging defects including skeletal alterations and lipodystrophy (La Torre et al, 2018 ). AKTIP/Ft1 interacts with lamins (Burla et al, 2016a , b ), pivotal elements for the control of nuclear architecture and DNA function, including DNA repair, replication and transcription (Dittmer and Misteli, 2011 ).…”