Article

The telosome/shelterin complex and its functions. Genome Bio 9:232

Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Baylor Plaza, Houston, TX 77030, USA.
Genome biology (Impact Factor: 10.81). 10/2008; 9(9):232. DOI: 10.1186/gb-2008-9-9-232
Source: PubMed

ABSTRACT

The telomeres that cap the ends of eukaryotic chromosomes serve a dual role in protecting the chromosome ends and in intracellular signaling for regulating cell proliferation. A complex of six telomere-associated proteins has been identified--the telosome or shelterin complex--that is crucial for both the maintenance of telomere structure and its signaling functions.

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    • "Telomeres are the repetitive DNA structures that protect the ends of linear chromosomes from nucleolytic degradation and attrition during DNA replication (reviewed in Blackburn, 2005, and Cech, 2004). The terminal repeats of telomeres are bound by a set of proteins, collectively termed Shelterin or the Telosome, which perform multiple functions in telomere maintenance that are essential for cellular division and genome stability (de Lange, 2005; Xin et al, 2008). Telomere repeat length is highly regulated, and a minimal repeat number is required to provide chromosome end protection (Suram & Herbig, 2014). "
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    ABSTRACT: Telomeres and tumor suppressor protein TP53 (p53) function in genome protection, but a direct role of p53 at telomeres has not yet been described. Here, we have identified non-canonical p53-binding sites within the human subtelomeres that suppress the accumulation of DNA damage at telomeric repeat DNA. These non-canonical subtelomeric p53-binding sites conferred transcription enhancer-like functions that include an increase in local histone H3K9 and H3K27 acetylation and stimulation of subtelomeric transcripts, including telomere repeat-containing RNA (TERRA). p53 suppressed formation of telomere-associated γH2AX and prevented telomere DNA degradation in response to DNA damage stress. Our findings indicate that p53 provides a direct chromatin-associated protection to human telomeres, as well as other fragile genomic sites. We propose that p53-associated chromatin modifications enhance local DNA repair or protection to provide a previously unrecognized tumor suppressor function of p53.
    Full-text · Article · Dec 2015 · The EMBO Journal
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    • "Telomeres are specialized protein–DNA structures at the ends of chromosomes (Blackburn, 2001; Palm & de Lange, 2008), whose dysfunction has been linked to genome instability, aging, and diseases such as cancer (Blackburn, 2001; Feldser et al., 2003; Martinez & Blasco, 2010; Shay & Wright, 2011; Lopez-Otin et al., 2013). In mammalian cells, the six-protein complex composed of TRF1, TRF2, RAP1, TIN2, TPP1, and POT1 (referred to as the telosome/shelterin) is central to ensuring telomere integrity, protecting telomeres from being recognized as DNA breaks, and coordinating telomerase-dependent maintenance of telomere length (Liu et al., 2004; de Lange, 2005; Palm & de Lange, 2008; Xin et al., 2008). Disruption of the telosome/shelterin complex and inhibition of its subunits can lead to telomere dysfunction-induced foci (TIFs), telomere recombination, chromosome end-to-end fusions, and ultimately cell senescence and death (van Steensel et al., 1998; Takai et al., 2003; Wu et al., 2006; Deng et al., 2008; Kim et al., 2008; Fumagalli et al., 2012; van Tuyn & Adams, 2012; Martinez et al., 2014). "
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    ABSTRACT: Telomeric repeat binding factor 2 (TRF2) is essential for telomere maintenance and has been implicated in DNA damage response and aging. Telomere dysfunction induced by TRF2 inhibition can accelerate cellular senescence in human fibroblasts. While previous work has demonstrated that a variety of factors can regulate TRF2 expression transcriptionally and post-translationally, whether microRNAs (miRNAs) also participate in post-transcriptionally modulating TRF2 levels remains largely unknown. To better understand the regulatory pathways that control TRF2, we carried out a large-scale luciferase reporter screen using a miRNA expression library and identified four miRNAs that could target human TRF2 and significantly reduce the level of endogenous TRF2 proteins. In particular, our data revealed that miR-23a could directly target the 3' untranslated region (3'UTR) of TRF2. Overexpression of miR-23a not only reduced telomere-bound TRF2 and increased telomere dysfunction-induced foci (TIFs), but also accelerated senescence of human fibroblast cells, which could be rescued by ectopically expressed TRF2. Our findings demonstrate that TRF2 is a specific target of miR-23a, and uncover a previously unknown role for miR-23a in telomere regulation and cellular senescence. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Full-text · Article · Mar 2015 · Aging cell
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    • "Given the population specificity of genetic variants associated with telomeres previously analyzed, we replicated significant results in a northern Italian population, in order to evaluate whether our results could be generalized. In particular, we analyzed, together with the TERC and TERT, some of the genes which are not directly involved in telomere elongation but are essential for telomere stability and structure (Kaminker et al. 2001; Xin et al. 2008). Among these, TEP1 specifically interacts with the telomerase RNA; TERF1, TERF2 and TERF2IP are located in the shelterin-complex that protects the telomeres from degradation and inappropriate DNA repair, prevents end-to-end fusion, atypical recombination, and premature senescence; TNKS and TNKS2 are other important telomere-associated proteins associated with telomeric DNA. "
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    ABSTRACT: Leukocyte telomere length (LTL) has been observed to be hereditable and correlated with longevity. However, contrasting results have been reported in different populations on the value of LTL heritability and on how biology of telomeres influences longevity. We investigated whether the variability of genes correlated to telomere maintenance is associated with telomere length and affects longevity in a population from Southern Italy (20-106 years). For this purpose we analyzed thirty-one polymorphisms in eight telomerase-associated genes of which twelve in the genes coding for the core enzyme (TERT and TERC) and the remaining in genes coding for components of the telomerase complex (TERF1, TERF2, TERF2IP, TNKS, TNKS2 and TEP1). We did not observe (after correcting for multiple testing) statistically significant associations between SNPs and LTL, possibly suggesting a low genetic influence of the variability of these genes on LTL in the elderly. On the other hand, we found that the variability of genes encoding for TERF1 and TNKS2, not directly involved in LTL, but important for keeping the integrity of the structure, shows a significant association with longevity. This suggests that the maintenance of these chromosomal structures may be critically important for preventing, or delaying, senescence and aging. Such a correlation was not observed in a population from northern Italy that we used as an independent replication set. This discrepancy is in line with previous reports regarding both the population specificity of results on telomere biology and the differences of aging in northern and southern Italy.
    Full-text · Article · Jan 2015 · Biogerontology
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