Telomerase Efficiently Elongates Highly Transcribing Telomeres in Human Cancer Cells

RNA polymerase II transcribes the physical ends of linear eukaryotic chromosomes into a variety of long non-coding RNA molecules including telomeric repeat-containing RNA (TERRA). Since TERRA discovery, advances have been made in the characterization of TERRA biogenesis and regulation; on the contrary its associated functions remain elusive. Most of the biological roles so far proposed for TERRA are indeed based on in vitro experiments carried out using short TERRA-like RNA oligonucleotides. In particular, it has been suggested that TERRA inhibits telomerase activity. We have exploited two alternative cellular systems to test whether TERRA and/or telomere transcription influence telomerase-mediated telomere elongation in human cancer cells. In cells lacking the two DNA methyltransferases DNMT1 and DNMT3b, TERRA transcription and steady-state levels are greatly increased while telomerase is able to elongate telomeres normally. Similarly, telomerase can efficiently elongate transgenic inducible telomeres whose transcription has been experimentally augmented. Our data challenge the current hypothesis that TERRA functions as a general inhibitor of telomerase and suggest that telomere length homeostasis is maintained independently of TERRA and telomere transcription

Precise Masses in the WASP-47 System

We present precise radial velocity observations of WASP-47, a star known to host a hot Jupiter, a distant Jovian companion, and, uniquely, two additional transiting planets in short-period orbits: a super-Earth in a ~19 hour orbit, and a Neptune in a ~9 day orbit. We analyze our observations from the HARPS-N spectrograph along with previously published data to measure the most precise planet masses yet for this system. When combined with new stellar parameters and reanalyzed transit photometry, our mass measurements place strong constraints on the compositions of the two small planets. We find unlike most other ultra-short-period planets, the inner planet, WASP-47 e, has a mass (6.83 +/- 0.66 Me) and radius (1.810 +/- 0.027 Re) inconsistent with an Earth-like composition. Instead, WASP-47 e likely has a volatile-rich envelope surrounding an Earth-like core and mantle. We also perform a dynamical analysis to constrain the orbital inclination of WASP-47 c, the outer Jovian planet. This planet likely orbits close to the plane of the inner three planets, suggesting a quiet dynamical history for the system. Our dynamical constraints also imply that WASP-47 c is much more likely to transit than a geometric calculation would suggest. We calculate a transit probability for WASP-47 c of about 10%, more than an order of magnitude larger than the geometric transit probability of 0.6%.Comment: 15 pages, 3 figures, 3 tables. Accepted in A

Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers.

Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility