The Role of RNA Editing in Cancer Development and Metabolic Disorders

Numerous human diseases arise from alterations of genetic information, most notably DNA mutations. Thought to be merely the intermediate between DNA and protein, changes in RNA sequence were an afterthought until the discovery of RNA editing 30 years ago. RNA editing alters RNA sequence without altering the sequence or integrity of genomic DNA. The most common RNA editing events are A-to-I changes mediated by adenosine deaminase acting on RNA (ADAR), and C-to-U editing mediated by apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (APOBEC1). Both A-to-I and C-to-U editing were first identified in the context of embryonic development and physiological homeostasis. The role of RNA editing in human disease has only recently started to be understood. In this review, the impact of RNA editing on the development of cancer and metabolic disorders will be examined. Distinctive functions of each RNA editase that regulate either A-to-I or C-to-U editing will be highlighted in addition to pointing out important regulatory mechanisms governing these processes. The potential of developing novel therapeutic approaches through intervention of RNA editing will be explored. As the role of RNA editing in human disease is elucidated, the clinical utility of RNA editing targeted therapies will be needed. This review aims to serve as a bridge of information between past findings and future directions of RNA editing in the context of cancer and metabolic disease

ARF and p53 coordinate tumor suppression of an oncogenic IFN-β-STAT1-ISG15 signaling axis

SummaryThe ARF and p53 tumor suppressors are thought to act in a linear pathway to prevent cellular transformation in response to various oncogenic signals. Here, we show that loss of p53 leads to an increase in ARF protein levels, which function to limit the proliferation and tumorigenicity of p53-deficient cells by inhibiting an IFN-β-STAT1-ISG15 signaling axis. Human triple-negative breast cancer (TNBC) tumor samples with coinactivation of p53 and ARF exhibit high expression of both STAT1 and ISG15, and TNBC cell lines are sensitive to STAT1 depletion. We propose that loss of p53 function and subsequent ARF induction creates a selective pressure to inactivate ARF and propose that tumors harboring coinactivation of ARF and p53 would benefit from therapies targeted against STAT1 and ISG15 activation

Multiple myeloma-associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress

10.1172/JCI63051Journal of Clinical Investigation12282793-2806JCIN

Acetate Promotes T Cell Effector Function during Glucose Restriction.

Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer

Operational experience with the GEM detector assembly lines for the CMS forward muon upgrade

The CMS Collaboration has been developing large-area triple-gas electron multiplier (GEM) detectors to be installed in the muon Endcap regions of the CMS experiment in 2019 to maintain forward muon trigger and tracking performance at the High-Luminosity upgrade of the Large Hadron Collider (LHC); 10 preproduction detectors were built at CERN to commission the first assembly line and the quality controls (QCs). These were installed in the CMS detector in early 2017 and participated in the 2017 LHC run. The collaboration has prepared several additional assembly and QC lines for distributed mass production of 160 GEM detectors at various sites worldwide. In 2017, these additional production sites have optimized construction techniques and QC procedures and validated them against common specifications by constructing additional preproduction detectors. Using the specific experience from one production site as an example, we discuss how the QCs make use of independent hardware and trained personnel to ensure fast and reliable production. Preliminary results on the construction status of CMS GEM detectors are presented with details of the assembly sites involvement

Differential limit on the extremely-high-energy cosmic neutrino flux in the presence of astrophysical background from nine years of IceCube data

We report a quasi-differential upper limit on the extremely-high-energy (EHE) neutrino flux above $5\times 10^{6}$ GeV based on an analysis of nine years of IceCube data. The astrophysical neutrino flux measured by IceCube extends to PeV energies, and it is a background flux when searching for an independent signal flux at higher energies, such as the cosmogenic neutrino signal. We have developed a new method to place robust limits on the EHE neutrino flux in the presence of an astrophysical background, whose spectrum has yet to be understood with high precision at PeV energies. A distinct event with a deposited energy above $10^{6}$ GeV was found in the new two-year sample, in addition to the one event previously found in the seven-year EHE neutrino search. These two events represent a neutrino flux that is incompatible with predictions for a cosmogenic neutrino flux and are considered to be an astrophysical background in the current study. The obtained limit is the most stringent to date in the energy range between $5 \times 10^{6}$ and $5 \times 10^{10}$ GeV. This result constrains neutrino models predicting a three-flavor neutrino flux of $E_\nu^2\phi_{\nu_e+\nu_\mu+\nu_\tau}\simeq2\times 10^{-8}\ {\rm GeV}/{\rm cm}^2\ \sec\ {\rm sr}$at$10^9\ {\rm GeV}$. A significant part of the parameter-space for EHE neutrino production scenarios assuming a proton-dominated composition of ultra-high-energy cosmic rays is excluded.Comment: The version accepted for publication in Physical Review

Book Reviews

With the observation of high-energy astrophysical neutrinos by the IceCube Neutrino Observatory, interest has risen in models of PeV-mass decaying dark matter particles to explain the observed flux. We present two dedicated experimental analyses to test this hypothesis. One analysis uses 6 years of IceCube data focusing on muon neutrino ‘track’ events from the Northern Hemisphere, while the second analysis uses 2 years of ‘cascade’ events from the full sky. Known background components and the hypothetical flux from unstable dark matter are fitted to the experimental data. Since no significant excess is observed in either analysis, lower limits on the lifetime of dark matter particles are derived: we obtain the strongest constraint to date, excluding lifetimes shorter than $10^{28}$ s at 90% CL for dark matter masses above 10 TeV