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HSF1 promotes TERRA transcription and telomere protection upon heat stress

Abstract : In response to metabolic or environmental stress, cells rapidly activate powerful defense mechanisms to prevent the formation and accumulation of toxic protein aggregates. The main orchestrator of this cellular response is HSF1 (Heat Shock Factor 1), a transcription factor involved in the up-regulation of protein-coding genes with protective roles. However, it is now becoming clear, that HSF1 function extends beyond what was previously predicted and that HSF1 can contribute to pericentromeric heterochromatin remodeling and activation as well as to efficiently support malignancy. In this study, we identify subtelomeric DNA as a new genomic target of HSF1 upon heat shock (HS). We show that HSF1 binding to subtelomeric regions plays an essential role in the upregulation of TERRA lncRNAs transcription and in the accumulation of repressive H3K9me3 histone mark at telomeres upon HS. Additionally, we demonstrate that HS significantly affects telomere capping and telomere integrity. We bring evidence of a partial TRF2 telomeric-binding factor dissociation and we reveal an accumulation of DNA damage at telomeres using the DNA damage marker H2A.X-P. In line with this, we bring solid evidences that under heat shock, HSF1 contributes to preserve telomere integrity by significantly limiting telomeric DNA damage accumulation. Altogether, our findings therefore reveal a new direct and essential function of HSF1 in transcription activation of TERRA and in telomere protection upon stress in human cancer cell lines. This work provides new insights into how telomeres are preserved under stressful heat shock conditions and allow us to propose a model where HSF1 may exert its protective function at telomeres via the expression of TERRA ncRNAs. Based on our results and given the important role of HSF1 in tumor development, defining the role of HSF1 with regard to telomere stability in tumor development already emerges as a promising challenge.
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Sivan Koskas. HSF1 promotes TERRA transcription and telomere protection upon heat stress. Development Biology. Université Grenoble Alpes, 2016. English. ⟨NNT : 2016GREAV052⟩. ⟨tel-01685262⟩

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