Environmental Stresses Disrupt Telomere Length Homeostasis

Romano, Gal Hagit; Harari, Yaniv; Yehuda, Tal; Podhorzer, Ariel; Rubinstein, Linda; Shamir, Ron; Gottlieb, Assaf; Silberberg, Yael; Pe’er, Dana; Ruppin, Eytan; Sharan, Roded; Kupiec, Martin

doi:10.1371/journal.pgen.1003721

Cited by 96 publications

(98 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…8A). Since steady-state telomere length decreases upon growth at an elevated temperature in wild-type yeast strains (69), these data suggest that the exaggerated decrease in telomere length that occurred in the noncomplemented strain was specifically attributable to decreased SRP1 function.…”

Section: the Est1-mut123(fl) Mutant (Bottom) Fluorescence Microsmentioning

confidence: 85%

Normal Telomere Length Maintenance in Saccharomyces cerevisiae Requires Nuclear Import of the Ever Shorter Telomeres 1 (Est1) Protein via the Importin Alpha Pathway

Hawkins

Friedman

2014

Eukaryot Cell

View full text Add to dashboard Cite

The Est1 (ever shorter telomeres 1) protein is an essential component of yeast telomerase, a ribonucleoprotein complex that restores the repetitive sequences at chromosome ends (telomeres) that would otherwise be lost during DNA replication. Previous work has shown that the telomerase RNA component (TLC1) transits through the cytoplasm during telomerase biogenesis, but mechanisms of protein import have not been addressed. Here we identify three nuclear localization sequences (NLSs) in Est1p. Mutation of the most N-terminal NLS in the context of full-length Est1p reduces Est1p nuclear localization and causes telomere shortening-phenotypes that are rescued by fusion with the NLS from the simian virus 40 (SV40) large-T antigen. In contrast to that of the TLC1 RNA, Est1p nuclear import is facilitated by Srp1p, the yeast homolog of importin ␣. The reduction in telomere length observed at the semipermissive temperature in a srp1 mutant strain is rescued by increased Est1p expression, consistent with a defect in Est1p nuclear import. These studies suggest that at least two nuclear import pathways are required to achieve normal telomere length homeostasis in yeast.T elomeres, the heterochromatic, G/T-rich regions of DNA located at the ends of linear chromosomes, are dynamic structures that undergo multiple rounds of attrition and elongation over the lifetimes of many eukaryotic cells. Because telomeres provide an essential capping function that protects DNA ends and aids in the maintenance of genomic stability, most eukaryotes use the enzyme telomerase to elongate telomeres (1).Telomerase is a ribonucleoprotein complex in which the RNA subunit interacts with a specialized reverse transcriptase to synthesize telomeric DNA. In the yeast Saccharomyces cerevisiae, telomerase minimally consists of the TLC1 RNA, which contains the template for nucleotide addition, and three ever shorter telomere (EST) proteins (2-5). Est2p is the reverse transcriptase that, together with TLC1 RNA, is necessary and sufficient for enzyme activity in vitro (6, 7). Est1p and Est3p are essential regulatory components that stimulate the in vitro activity of telomerase and have been implicated in the recruitment and/or activation of telomerase at the telomere (5,6,8,9).Interactions between the subunits of telomerase and between telomerase and the telomere are complex. Est1p interacts with the single-stranded telomeric DNA binding protein, Cdc13p (10, 11). Ectopic expression of a Cdc13-Est2 fusion protein bypasses the requirement for EST1, suggesting that Est1p recruits telomerase to the telomere through the interaction with Cdc13p (12). TLC1 RNA possesses distinct binding sites for Est1p and Est2p, suggesting that the interaction between Est1p and Est2p is mediated by the telomerase RNA in vivo (13-16). However, an RNA-independent interaction between Est1p and Est2p has been observed (8). In live cells, persistent foci of TLC1 RNA are detected at telomeres during S phase-a phenotype greatly reduced in cells harboring the cdc13-2 mutation, in which t...

show abstract

Section: the Est1-mut123(fl) Mutant (Bottom) Fluorescence Microsmentioning

confidence: 85%

Normal Telomere Length Maintenance in Saccharomyces cerevisiae Requires Nuclear Import of the Ever Shorter Telomeres 1 (Est1) Protein via the Importin Alpha Pathway

Hawkins

Friedman

2014

Eukaryot Cell

View full text Add to dashboard Cite

show abstract

“…In this respect, physiological pathways and mechanisms for bio-behavioral factors and cancer progression was reviewed (Lutgendorf et al 2011). In addition, molecular study with telomerase activity associated telomere length with environmental and psychological stress (Epel et al 2010;Romano et al 2013). A result of interest, however, was recently published demonstrating that the effects of personality traits and depression on cancer risk and survival appear to be extremely as small as the data obtained from prospective cohort studies in population-based and clinical databases Nakaya 2014).…”

Section: Discussionmentioning

confidence: 99%

Psychological stress and cancer

Soung

Kim

2015

J Anal Sci Technol

View full text Add to dashboard Cite

Psychological or psychosocial stress has been emerging as one of the key factors associated with cancer initiation, growth, and metastasis. Accumulating data, however, has mainly focused on cancer progression due to the inconsistent results of cancer etiology caused by emotional stress. Depression is closely linked to stress and induces hypothalamic-pituitary-adrenal (HPA) axis activation as well as sympathetic nervous system (SNS) down to immune cell surveillance. This review briefly describes the activation of neuroendocrine system by psychological stress/ depression and its effect on cancer occurrence and metastasis, which may be useful for the design of new cancer treatments.

show abstract

“…2H). It was previously reported that prolonged heat shock (at 37°C) causes telomere shortening in yeast (32,33). To understand whether telomere shortening is responsible for the derepression of subtelomeric chromatin, we wanted to find out whether transient heat shock also leads to such changes in the telomere structure.…”

Section: Hs or Hsp82 Overexpression Induces Transcriptional Downregulmentioning

confidence: 99%

“…An elongated telomere track leads to the increased inheritance of the silenced subtelomeric state and is independent of yeast chromatin assembly factor 1 (yCAF-1). In another study, it was reported that prolonged exposure to heat stress (37°C) as well as Hsp82 overexpression led to telomere shortening in wild-type cells (32,33). Thus, it is important to understand whether transient heat shock causes any change in telomere structure and can thereby influence telomere silencing.…”

Section: Figmentioning

confidence: 99%

Heat Stress-Induced Cup9-Dependent Transcriptional Regulation of SIR2

Laskar

Sheeba

Bhattacharyya

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

The epigenetic writer Sir2 maintains the heterochromatin state of chromosome in three chromosomal regions, namely, the silent mating type loci, telomeres, and the ribosomal DNA (rDNA). In this study, we demonstrated the mechanism by which Sir2 is regulated under heat stress. Our study reveals that a transient heat shock causes a drastic reduction in the SIR2 transcript which results in sustained failure to initiate silencing for as long as 90 generations. Hsp82 overexpression, which is the usual outcome of heat shock treatment, leads to a similar downregulation of SIR2 transcription. Using a series of genetic experiments, we have established that heat shock or Hsp82 overexpression causes upregulation of CUP9 that, in turn, represses SIR2 transcription by binding to its upstream activator sequence. We have mapped the cis regulatory element of SIR2. Our study shows that the deletion of cup9 causes reversal of the Hsp82 overexpression phenotype and upregulation of SIR2 expression in heat-induced Hsp82-overexpressing cells. On the other hand, we found that Cup9 overexpression represses SIR2 transcription and leads to a failure in the establishment of heterochromatin. The results of our study highlight the mechanism by which environmental factors amend the epigenetic configuration of chromatin.

show abstract

Environmental Stresses Disrupt Telomere Length Homeostasis

Cited by 96 publications

References 55 publications

Normal Telomere Length Maintenance in Saccharomyces cerevisiae Requires Nuclear Import of the Ever Shorter Telomeres 1 (Est1) Protein via the Importin Alpha Pathway

Normal Telomere Length Maintenance in Saccharomyces cerevisiae Requires Nuclear Import of the Ever Shorter Telomeres 1 (Est1) Protein via the Importin Alpha Pathway

Psychological stress and cancer

Heat Stress-Induced Cup9-Dependent Transcriptional Regulation of SIR2

Contact Info

Product

Resources

About