TELOMERES EXPRESS THEIR LNCRNAS TERRA AND RECRUIT FKBP51 IN RESPONSE TO INCREASED ROS DURING THE EPITHELIAL-TO-MESENCHYMAL TRANSITION

GALIGNIANA N.M.; PIWIEN PILIPUK, G.; URANGA, R.

Mar del Plaa

Congreso; Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2022

Sociedad Argentina de Investigación Clínica

We have previously shown that telomeric lncRNAs TERRA increase by oxidative stress to protect the genome upon DNA damage. The epithelial-to-mesenchymal transition (EMT) plays an important role in the progression of primary epithelial tumors, and it was shown that ROS favor EMT. Thus, we hypothesize that the inherent rise in ROS during EMT triggers TERRA induction. We found that TERRA levels increase when NMuMG epithelial cells undergo EMT with TGFbeta1 treatment for 4 days. These cells have over 4-fold induction of telomere DNA damage (TAFs) than in their epithelial state, and TAFs co-localize with stress protein FKBP51. When NMuMG are treated with TGFbeta1 + 100µM H2O2, EMT is accelerated, evident at day 1, and accompanied by earlier TERRA induction and higher number of TAFs with FKBP51 co-localization than in EMT triggered by TGFbeta1 alone, suggesting that earlier TERRA induction is required for protecting telomeres from damage. Accordingly, ChIP shows higher FKBP51 recruitment to subtelomeric regions when EMT is triggered by TGFbeta1 in the presence of H2O2 than in its absence, suggesting FKBP51 is relevant for TERRA induction. HP1gamma, RNA-POL II and lamin A/C display the same recruitment pattern. FKBP51 co-immunoprecipitates with lamin A/C. Since FKBP51 lacks a DNA-binding domain, lamins may act as scaffolds for FKBP51 recruitment to subtelomeres. In conclusion, EMT induces TERRAs upon the onset of TAF formation where FKBP51 is recruited, partly through its interaction with lamin A/C, events that are magnified in a milieu of higher ROS levels that accelerates EMT