Nuclear respiratory factor 1 and endurance exercise promote human telomere transcription

Diman, Aurélie; Boros, Joanna; Poulain, Florian; Rodriguez, Julie; Purnelle, Marin; Episkopou, Harikleia; Bertrand, Luc; Francaux, Marc; Deldicque, Louise; Decottignies, Anabelle

doi:10.1126/sciadv.1600031

Cited by 86 publications

(92 citation statements)

References 45 publications

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“…To investigate single-telomere TERRA molecules in human cancer cells, we employed the CRISPR/Cas9 genome editing tool to promote site-specific integration of a cassette containing 10×MS2 repeats and a neomycin resistance gene flanked by lox-p sites (TERRA-MS2 cassette) at subtelomere 15q in AGS cells, which is a human stomach adenocarcinoma cell line. The subtelomere 15q was chosen since expression of TERRA from human telomere 15q has been extensively validated by in vitro techniques [12,16,18,28]. The 15q subtelomere contains a conserved CpG rich TERRA promoter region and the TERRA transcription start sites within this subtelomere have been mapped [7,18].…”

Section: Resultsmentioning

confidence: 99%

“…For this reason, TERRA molecules consist of subtelomere derived sequences at their 5′ end, and their 3′end includes arrays of UUAGGG repeats (reviewed in [8]). Expression of TERRA is tightly regulated by the activity of several transcription regulators, including the chromatin organizing factor CTCF [9] and the transcription factors heat shock factor 1 (HSF1) [10], Snail [11], as well as the nuclear respiratory factor NRF1 [12]. Furthermore, telomere shortening is associated with increased TERRA levels in yeast as well as human cells [13-16].…”

Section: Introductionmentioning

confidence: 99%

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Live-cell imaging reveals the dynamics and function of single-telomere TERRA molecules in cancer cells

et al. 2018

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Telomeres cap the ends of eukaryotic chromosomes, protecting them from degradation and erroneous recombination events which may lead to genome instability. Telomeres are transcribed giving rise to telomeric repeat-containing RNAs, called TERRA. The TERRA long noncoding RNAs have been proposed to play important roles in telomere biology, including heterochromatin formation and telomere length homeostasis. While TERRA RNAs are predominantly nuclear and localize at telomeres, little is known about the dynamics and function of TERRA molecules expressed from individual telomeres. Herein, we developed an assay to image endogenous TERRA molecules expressed from a single telomere in living human cancer cells. We show that single-telomere TERRA can be detected as TERRA RNA single particles which freely diffuse within the nucleus. Furthermore, TERRA molecules aggregate forming TERRA clusters. Three-dimensional size distribution and single particle tracking analyses revealed distinct sizes and dynamics for TERRA RNA single particles and clusters. Simultaneous time lapse confocal imaging of TERRA particles and telomeres showed that TERRA clusters transiently co-localize with telomeres. Finally, we used chemically modified antisense oligonucleotides to deplete TERRA molecules expressed from a single telomere. Single-telomere TERRA depletion resulted in increased DNA damage at telomeres and elsewhere in the genome. These results suggest that single-telomere TERRA transcripts participate in the maintenance of genomic integrity in human cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Live-cell imaging reveals the dynamics and function of single-telomere TERRA molecules in cancer cells

et al. 2018

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“…Assuming that the majority of TRLs form cotranscriptionally, can we expect the subtelomeric component of TERRA to influence TRL formation? Most TERRA promoters are embedded in regions positioned within 2 kb of the telomere tract , although TERRA promoters positioned 5–10 kb from the telomere tract have been described for several human telomeres . Despite sharing high sequence similarity , a bioinformatic analysis of the distal 2 kb of the majority of human chromosome ends revealed that subtelomeres differ in characteristics such as CpG richness, GC content, and GC‐skewing .…”

Section: Telomere R‐loops In Mammalsmentioning

confidence: 99%

Section: How Do Subtelomeric Regions Contribute To Trl Formation?mentioning

confidence: 99%

DNA:RNA hybrids at telomeres – when it is better to be out of the (R) loop

Toubiana

Selig

2018

The FEBS Journal

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R-loops (RLs) are three-stranded nucleic acid structures that contain a DNA:RNA hybrid and a displaced DNA strand. Genomic regions with GC skew and a G-rich transcript are particularly prone to form RLs. RLs play important physiological roles in cells; however, when present at abnormally high levels, they may threaten genome stability. The perfect GC skew of telomeric repeats and the discovery of telomeric repeat-containing RNA (TERRA), a long noncoding transcript that consists of the G-rich telomeric sequence, make telomeric sequences the perfect candidates for generating RLs. Indeed, in the past 5 years, telomere R-loops (TRLs) have been demonstrated in Saccharomyces cerevisiae, Trypanosoma brucei, and human cells. The presence of TRLs in normal human cells that transcribe low levels of TERRA, suggests a physiological role for these nucleic structures in telomere maintenance. Abnormally enhanced TERRA transcription, as found in several human pathological conditions, leads to high TRL levels and various cellular outcomes, depending on the recombinogenic capabilities of the cells. Study of TRLs in various organisms highlights the necessity for tight regulation of these structures, which can switch from beneficial to detrimental under different conditions. Here, we review the current state of knowledge on TRLs, describe several means by which TRLs are regulated, and discuss how findings from yeast are relevant to human pathological scenarios in which TRLs are deregulated.

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“…The report of Jarosch et al (2016) and many others highlight the fact that mitochondrial signaling plays a functional role in promoting exercise efficiency. Both NRF-1 and PGC1α stimulate human telomere transcription in response to exercise via AMPK activation, connecting telomere protection in aging with metabolism (Diman et al, 2016). Increase in the ADP/ATP ratio that follows physical activity induces AMPK activity in muscle, and, in so doing, regulates the β-oxidation capacity of muscle and mitochondrial biogenesis (Winder et al, 1997; Zong et al, 2002).…”

Section: Muscle Metabolism In Agingmentioning

confidence: 99%

Influence of anaerobic and aerobic exercise on age-related pathways in skeletal muscle

Navas-Enamorado

Bernier

Brea-Calvo

et al. 2017

Ageing Research Reviews

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Nuclear respiratory factor 1 and endurance exercise promote human telomere transcription

Abstract: The AMPK/PGC-1α metabolic pathway and nuclear respiratory factor 1 up-regulate human telomere transcription.

Cited by 86 publications

References 45 publications

Live-cell imaging reveals the dynamics and function of single-telomere TERRA molecules in cancer cells

Live-cell imaging reveals the dynamics and function of single-telomere TERRA molecules in cancer cells

DNA:RNA hybrids at telomeres – when it is better to be out of the (R) loop

Influence of anaerobic and aerobic exercise on age-related pathways in skeletal muscle

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