A role for heterochromatin protein 1 at human telomeres

Molecular Pathogenesis Program, Department of Pathology, Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
Genes & development (Impact Factor: 10.8). 08/2011; 25(17):1807-19. DOI: 10.1101/gad.17325211
Source: PubMed


Human telomere function is mediated by shelterin, a six-subunit complex that is required for telomere replication, protection, and cohesion. TIN2, the central component of shelterin, has binding sites to three subunits: TRF1, TRF2, and TPP1. Here we identify a fourth partner, heterochromatin protein 1γ (HP1γ), that binds to a conserved canonical HP1-binding motif, PXVXL, in the C-terminal domain of TIN2. We show that HP1γ localizes to telomeres in S phase, where it is required to establish/maintain cohesion. We further demonstrate that the HP1-binding site in TIN2 is required for sister telomere cohesion and can impact telomere length maintenance by telomerase. Remarkably, the PTVML HP1-binding site is embedded in the recently identified cluster of mutations in TIN2 that gives rise to dyskeratosis congenita (DC), an inherited bone marrow failure syndrome caused by defects in telomere maintenance. We show that DC-associated mutations in TIN2 abrogate binding to HP1γ and that DC patient cells are defective in sister telomere cohesion. Our data indicate a novel requirement for HP1γ in the establishment/maintenance of cohesion at human telomeres and, furthermore, may provide insight into the mechanism of pathogenesis in TIN2-mediated DC.

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    • "Several recent reports dealing with human telomeres, however, question the unequivocal view of telomeres as heterochromatic structures: (i) the level of heterochromatic marks was surprisingly low in human fibroblast telomeres [O'Sullivan et al., 2010], and (ii) the telomeres of human T-cells were associated with euchromatic marks while heterochromatic H3K9me3 was under-represented [Rosenfeld et al., 2009]. Nevertheless, further data were recently presented supporting the significance of the heterochromatic character of human telomeres for proper telomere function and genome integrity [Canudas et al., 2011; Postepska-Igielska et al., 2013]. "
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    ABSTRACT: As chromatin structures, telomeres undergo epigenetic regulation of their maintenance and function. In plants, these processes are likely of a higher complexity than in animals or yeasts, as exemplified by methylation of cytosines in plant telomeric DNA or reversible developmental regulation of plant telomerase. We highlight the dual role of telomeres from the epigenetic point of view: (i) as chromatin structures that are the subject of epigenetic regulation (e.g. DNA and histone modifications), and (ii) as chromosome domains acting themselves as epigenetic regulatory elements (e.g. in the telomere position effect). Possibly, some molecular tools (e.g. telomeric transcripts) are common to both these aspects of telomere epigenetics. We further discuss the justification for the classical textbook view of telomeres as heterochromatic structures. © 2014 S. Karger AG, Basel.
    Cytogenetic and Genome Research 04/2014; 143(1-3). DOI:10.1159/000360775 · 1.56 Impact Factor
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    • "However, as telomere sister chromatid exchanges are elevated in TIN2−/− murine cells [7], perhaps phosphorylation is related to this aspect of TIN2 function. Alternatively, S295 and S330 reside close to mutation sites found in dyskeratosis congenital patients [33] that affect binding to heterochromatin protein 1γ and telomere length [34], thus perhaps mitotic phosphorylation of TIN2 is instead involved in telomere length regulation. Finally, as RSK2 phosphorylated TIN2, and inhibiting this kinase in mitotic cells reduced TIN2 phosphorylation, TIN2 phosphorylation may be linked with functions of RSK2. "
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    ABSTRACT: The protein TIN2 is a member of telomere-binding protein complex that serves to cap and protect mammalian chromosome ends. As a number of proteins in this complex are phosphorylated in a cell cycle-dependent manner, we investigated whether TIN2 is modified by phosphorylation as well. We performed phospho-proteomic analysis of human TIN2, and identified two phosphorylated residues, serines 295 and 330. We demonstrated that both these sites were phosphorylated during mitosis in human cells, as detected by Phos-tag reagent and phosphorylation-specific antibodies. Phosphorylation of serines 295 and 330 appeared to be mediated, at least in part, by the mitotic kinase RSK2. Specifically, phosphorylation of TIN2 at both these residues was increased upon expression of RSK2 and reduced by an inhibitor of the RSK family of kinases. Moreover, RSK2 phosphorylated TIN2 in vitro. The identification of these specifically timed post-translational events during the cell cycle suggests a potential mitotic regulation of TIN2 by phosphorylation.
    PLoS ONE 08/2013; 8(8):e71697. DOI:10.1371/journal.pone.0071697 · 3.23 Impact Factor
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    • "The structure of HP1 contains an evolutionarily conserved chromodomain that binds to a methylated lysine on histone H3 (H3K9me) [7]. This binding epigenetically marks regions of silenced or reduced gene expression [8]. HP1 stabilizes telomeric and centromeric heterochromatin structure and facilitates DNA repair after disruption or damage [9,10]. "
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    ABSTRACT: Background Aberrant chromatin structure in cancer cells results from altered proteins involved in its packaging. Heterochromatin protein 1 gamma (HP1γ) is a non-histone heterochromatic protein that functions to maintain chromatin stability and is important in embryonic development. Given an interest in the role developmental genes play in cancer, we investigated HP1γ expression in prostate cancer (PCa) and its prognostic associations. Methods Tissue microarrays consisting of benign (N = 96), localized cancer (N = 146), metastatic PCa (N = 44), and HGPIN (N = 50) were immunoflourescently stained for HP1γ and Ki-67. Using a novel, automated quantitative imaging system, VECTRA™, epithelial staining in both the nucleus and cytoplasm was quantified and compared against clinicopathologic variables. Results HP1γ is significantly elevated in HGPIN (80%), localized PCa (76%), and metastatic PCa (98%) compared to benign tissues from both the nuclear and cytoplasmic compartments (P < 0.0001). Increased nuclear and total HP1γ expression was associated with Gleason score (P = 0.02 and P = 0.04 respectively). Given known binding to the C-terminus of Ki-67, a co-expression analysis was performed that revealed a correlation between nuclear and cytoplasmic HP1γ and Ki-67 (Pearson Coefficient 0.321 and 0.562 respectively, P < 0.0001). Cox survival analysis demonstrated that cytoplasmic HP1γ expression was an independent prognostic marker and out-performed pathological Gleason score for predicting PSA-recurrence after radical prostatectomy. Conclusions In this first detailed analysis of HP1γ expression in cancer, VECTRA™ demonstrates compartmentalized and total HP1γ protein expression is increased in PCa and that expression correlates with clinical outcomes better than Gleason score. Given the critical role HP1γ plays in chromatin organization and gene expression, it represents a novel prognostic and therapeutic target.
    BMC Cancer 03/2013; 13(1):148. DOI:10.1186/1471-2407-13-148 · 3.36 Impact Factor
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