Article

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

ABSTRACT

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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    • "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.
    Preview · Article · Aug 2013 · PLoS ONE
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    • "Conversely, depletion of SA2, but not SA1 or TIN2, led to a defect in centromere cohesion (Canudas and Smith, 2009). Additional studies showed that the heterochromatin protein HP1c associated with TIN2 and was required for cohesion at telomeres, but not at centromeres (Canudas et al., 2011). "
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    ABSTRACT: Sister chromatid cohesion relies on cohesin, a complex comprised of a tri-partite ring and a peripheral subunit Scc3, which is found as two related isoforms SA1 and SA2 in vertebrates. There is a division of labor between the vertebrate cohesin complexes; SA1-cohesin is required at telomeres and SA2-cohesin at centromeres. Depletion of SA1 has dramatic consequences for telomere function and genome integrity, but the mechanism by which SA1-cohesin mediates cohesion at telomeres is not well understood. Here we dissect the individual contribution of SA1 and the ring subunits to telomere cohesion and show that telomeres rely heavily on SA1 and to a lesser extent on the ring for cohesion. Using chromatin immunoprecipitation we show that SA1 is highly enriched at telomeres, is decreased at mitosis when cohesion is resolved, and is increased when cohesion persists. Overexpression of SA1 alone was sufficient to induce cohesion at telomeres, independent of the cohesin ring and dependent on its unique (not found in SA2) amino terminal domain, which we show binds to telomeric DNA via an AT-hook motif. We suggest that a specialized cohesion mechanism may be required to accommodate the high level of DNA replication-associated repair at telomeres.
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