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

Mattia La Torre (1) , Chiara Merigliano (1) , Romina Burla (1) , Carla Mottini (1) , Giorgia Zanetti (1) , Simona del Giudice (1) , Mariateresa Carcuro (1) , Ilaria Virdia (2) , Elisabetta Bucciarelli (3) , Isabella Manni (2) , Gianluca Rampioni Vinciguerra (4) , Giulia Piaggio (2) , Mara Riminucci (1) , Ana Cumano (5) , Armando Bartolazzi (4) , Fiammetta Vernì (1) , Silvia Soddu (2) , Maurizio Gatti (1, 3) , Isabella Saggio (1, 3)

1 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
2 IRE - IFO - Istituto Nazionale Tumori Regina Elena [Roma]
3 CNR - Consiglio Nazionale delle Ricerche [Roma]
4 Azienda Ospedaliera Sant'Andrea [Roma]
5 Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4) - Lymphopoïèse

Human 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 (Ft1kof/kof ) mice exhibit telomeric defects and that Ft1kof/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 (Ft1kof/kof ; p53ko/ko and Ft1kof/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.

Keywords: AKTIP; DNA damage; aging; lamins; progeria; telomeres

Domains: Life Sciences [q-bio]; Immunology

Mattia La Torre, Chiara Merigliano, Romina Burla, Carla Mottini, Giorgia Zanetti, et al.. Mice with reduced expression of the telomere-associated protein Ft1 develop p53-sensitive progeroid traits. Aging Cell, 2018, 17 (4), pp.e12730. ⟨10.1111/acel.12730⟩. ⟨pasteur-01768324⟩