Oxidative stress induces the expression of long non-coding RNAs from telomeres (TERRA) for telomeric protection

G. PIWIEN PILIPUK; N.M. GALIGNIANA

San Diego

Congreso; The 9th International Congress on Stress Responses in Biology & Medicine; 2019

Cell Stress Society International

Long non-coding RNAs transcribed from telomeres, known as TERRA (telomeric repeat-containing RNA), are associated with telomere and genome stability. TERRA expression is elevated in human cancer tissues, however little is known about their function. Oxidative stress damages biomolecules and activates signaling cascades involved in cell proliferation, apoptosis, and metastasis. Since telomeres are prone to oxidative damage leading to their dysfunction, our objective was to characterize TERRA expression in oxidative stress, and the mechanisms involved in their control. H2O2 induced TERRA expression in HEK-293T cells, and was prevented by antioxidant treatment. It was reported that ROS are increased in brown (BAT) but not in white adipose tissue of mice exposed to cold. Importantly, we found increased TERRAs only in BAT of mice exposed to cold. In HEK-293T cells exposed to H2O2, ChIP shows that chromatin landscape is modified favoring telomere transcription. TERRAs interacted with HP1a/g, both proteins found recruited to subtelomeres. Since HP1g interacts with the transcriptional machinery, TERRAs may stimulate their own expression by recruiting HP1g to subtelomeres. TERRA induction was lost within 2h after removal of H2O2 from culture medium, suggesting they have protective functions; however the chromatin landscape was kept unchanged maintaining the presence of RNAPolII, HP1s and levels of histone H4 acetylation permissive for transcription. Cells that overcome a first H2O2 challenge induce TERRAs faster upon a second exposure (5min vs. 4h), supporting the notion of their protective role. PKA inhibitor H89 blocks TERRA induction by H2O2 or forskolin-IBMX, suggesting that PKA participates in TERRA control. Treatment of cells with drugs that disrupt cytoskeleton integrity in a similar manner as H2O2 or growing cells on surfaces of different stiffness that generate differential cytoskeleton tension, also modified TERRA levels. In summary, we show for the first time that TERRAs are induced in response to oxidative stress and are regulated by PKA, as well as by changes in cytoskeleton dynamics.