Koskas Sivan, Decottignies Anabelle, Dufour Solenne, Pezet Mylène, Verdel André, Vourc'h Claire, Faure Virginie
University Grenoble Alpes, INSERM U1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38042 Grenoble Cedex 9, France.
De Duve Institute and Catholic University of Louvain, GEPI, 1200 Brussels, Belgium.
Nucleic Acids Res. 2017 Jun 20;45(11):6321-6333. doi: 10.1093/nar/gkx208.
In response to metabolic or environmental stress, cells 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. It has become very clear that HSF1 has a broader function than initially expected. Indeed, our previous work demonstrated that, upon stress, HSF1 activates the transcription of a non-coding RNA, named Satellite III, at pericentromeric heterochromatin. Here, we observe that the function of HSF1 extends to telomeres and identify subtelomeric DNA as a new genomic target of HSF1. We show that the binding of HSF1 to subtelomeric regions plays an essential role in the upregulation of non-coding TElomeric Repeat containing RNA (TERRA) transcription upon heat shock. Importantly, our data show that telomere integrity is impacted by heat shock and that telomeric DNA damages are markedly enhanced in HSF1 deficient cells. Altogether, our findings reveal a new direct and essential function of HSF1 in the transcriptional activation of TERRA and in telomere protection upon stress.
作为对代谢或环境应激的反应，细胞会激活强大的防御机制，以防止有毒蛋白质聚集体的形成和积累。这种细胞反应的主要协调者是热休克因子1（HSF1），它是一种转录因子，参与上调具有保护作用的蛋白质编码基因。现在已经非常清楚，HSF1的功能比最初预期的要广泛得多。事实上，我们之前的研究表明，在应激状态下，HSF1会激活位于着丝粒周围异染色质上的一种名为卫星III的非编码RNA的转录。在这里，我们观察到HSF1的功能扩展到了端粒，并确定亚端粒DNA是HSF1的一个新的基因组靶点。我们表明，HSF1与亚端粒区域的结合在热休克后上调含端粒重复序列的非编码RNA（TERRA）转录中起着至关重要的作用。重要的是，我们的数据表明端粒完整性受到热休克的影响，并且在HSF1缺陷细胞中端粒DNA损伤明显增强。总之，我们的研究结果揭示了HSF1在TERRA转录激活和应激时端粒保护方面的一种新的直接且重要的功能。
