A ‘higher order' of telomere regulation: telomere heterochromatin and telomeric RNAs

Protection of chromosome ends from DNA repair and degradation activities is mediated by specialized protein complexes bound to telomere repeats. Recently, it has become apparent that epigenetic regulation of the telomric chromatin template critically impacts on telomere function and telomere-length homeostasis from yeast to man. Across all species, telomeric repeats as well as the adjacent subtelomeric regions carry features of repressive chromatin. Disruption of this silent chromatin environment results in loss of telomere-length control and increased telomere recombination. In turn, progressive telomere loss reduces chromatin compaction at telomeric and subtelomeric domains. The recent discoveries of telomere chromatin regulation during early mammalian development, as well as during nuclear reprogramming, further highlights a central role of telomere chromatin changes in ontogenesis. In addition, telomeres were recently shown to generate long, non-coding RNAs that remain associated to telomeric chromatin and will provide new insights into the regulation of telomere length and telomere chromatin. In this review, we will discuss the epigenetic regulation of telomeres across species, with special emphasis on mammalian telomeres. We will also discuss the links between epigenetic alterations at mammalian telomeres and telomere-associated diseases

The origins of estrogen receptor alpha-positive and estrogen receptor alpha-negative human breast cancer

Current hormonal therapies have benefited millions of patients with breast cancer. Their success, however, is often temporary and limited to a subset of patients whose tumors express estrogen receptor alpha (ER). The therapies are entirely ineffective in ER-negative disease. Recent studies suggest that there are many biological pathways and alterations involved in determining whether ER is expressed and how it is regulated during breast cancer evolution. Improving hormonal therapies, in addition to perfecting current strategies, will also target these newly discovered pathways and alterations, and others yet to be found. The present commentary will briefly highlight a few important observations and unanswered questions regarding ER status and growth regulation during breast cancer evolution, which hopefully will help to stimulate new thinking and progress in this important area of medial research

The Candida albicans Ku70 Modulates Telomere Length and Structure by Regulating Both Telomerase and Recombination

The heterodimeric Ku complex has been shown to participate in DNA repair and telomere regulation in a variety of organisms. Here we report a detailed characterization of the function of Ku70 in the diploid fungal pathogen Candida albicans. Both ku70 heterozygous and homozygous deletion mutants have a wild-type colony and cellular morphology, and are not sensitive to MMS or UV light. Interestingly, we observed complex effects of KU70 gene dosage on telomere lengths, with the KU70/ku70 heterozygotes exhibiting slightly shorter telomeres, and the ku70 null strain exhibiting long and heterogeneous telomeres. Analysis of combination mutants suggests that the telomere elongation in the ku70 null mutant is due mostly to unregulated telomerase action. In addition, elevated levels of extrachromosomal telomeric circles were detected in the null mutant, consistent with activation of aberrant telomeric recombination. Altogether, our observations point to multiple mechanisms of the Ku complex in telomerase regulation and telomere protection in C. albicans, and reveal interesting similarities and differences in the mechanisms of the Ku complex in disparate systems

Probing the dust formation region in IRC +10216 with the high vibrational states of hydrogen cyanide

We report the detection in IRC +10216 of 63 rotational transitions of HCN, most of them with quantum numbers J = 3–2, pertaining to 28 different vibrational states with energies up to 10 700 K (ν1+3ν2+ν3). Some of the transitions were also observed for the rare isotopologue H13CN. The observations were carried out with the IRAM 30-m telescope. The HCN lines with level energies above 5000 K arise within 1.5 stellar radius from the photosphere. Their intensities imply a vibrational temperature of Tvib ≃ 2400 K and a fractional HCN abundance relative to H2, x(HCN) = 5–7 × 10-5. These high-energy levels are mainly populated by photospheric radiation, and their vibrational temperature yields a direct measurement of the stellar photospheric temperature. The lines with energy levels between 2000 and 5000 K yield Tvib ≃ 1300 K and x(HCN)  ≃  0.8–2 × 10-5. They are radiatively excited and arise from a shell extending between 1.5 and 5 stellar radii. Finally, the lines from the low-energy vibrational states (<2000 K) trace a larger region of the envelope (5–28 stellar radii) with Tvib = 400–600 K and x(HCN) = 4–6 × 10-6. They are strongly affected by mid and near-infrared pumping. The line widths increase from 5 km s-1 near the 2400 K photosphere, to 19 km s-1 in the warm 400 K shell. This provides a unique insight into the physical conditions of the gas acceleration and dust formation region