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Metabolic Regulation of the Epitranscriptome.
Thomas, JM, Batista, PJ, Meier, JL
ACS chemical biology. 2019;(3):316-324
Abstract
An emergent theme in cancer biology is that dysregulated energy metabolism may directly influence oncogenic gene expression. This is due to the fact that many enzymes involved in gene regulation use cofactors derived from primary metabolism, including acetyl-CoA, S-adenosylmethionine, and 2-ketoglutarate. While this phenomenon was first studied through the prism of histone and DNA modifications (the epigenome), recent work indicates metabolism can also impact gene regulation by disrupting the balance of RNA post-transcriptional modifications (the epitranscriptome). Here we review recent studies that explore how metabolic regulation of writers and erasers of the epitranscriptome (FTO, TET2, NAT10, MTO1, and METTL16) helps shape gene expression through three distinct mechanisms: cofactor inhibition, cofactor depletion, and writer localization. Our brief survey underscores similarities and differences between the metabolic regulation of the epigenome and epitranscriptome, and highlights fertile ground for future investigation.
2.
How do ADARs bind RNA? New protein-RNA structures illuminate substrate recognition by the RNA editing ADARs.
Thomas, JM, Beal, PA
BioEssays : news and reviews in molecular, cellular and developmental biology. 2017;(4)
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Abstract
Deamination of adenosine in RNA to form inosine has wide ranging consequences on RNA function including amino acid substitution to give proteins not encoded in the genome. What determines which adenosines in an mRNA are subject to this modification reaction? The answer lies in an understanding of the mechanism and substrate recognition properties of adenosine deaminases that act on RNA (ADARs). Our recent publication of X-ray crystal structures of the human ADAR2 deaminase domain bound to RNA editing substrates shed considerable light on how the catalytic domains of these enzymes bind RNA and promote adenosine deamination. Here we review in detail the deaminase domain-RNA contact surfaces and present models of how full length ADARs, bearing double stranded RNA-binding domains (dsRBDs) and deaminase domains, could process naturally occurring substrate RNAs.
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Systematic review: Health-related characteristics of elderly hospitalized adults and nursing home residents associated with short-term mortality.
Thomas, JM, Cooney, LM, Fried, TR
Journal of the American Geriatrics Society. 2013;(6):902-911
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Abstract
OBJECTIVES To identify the domains of health-related characteristics of older hospitalized adults and nursing home residents most strongly associated with short-term mortality. DESIGN Systematic review. SETTING Studies published in English in MEDLINE, Scopus, or Web of Science before August 1, 2010. PARTICIPANTS Prospective studies consisting of persons aged 65 and older that evaluated the association between at least one health-related participant characteristic and mortality within a year in multivariable analysis. MEASUREMENTS All health-related characteristics associated with mortality in multivariable analysis were extracted and categorized into domains. The frequency, with all studies combined, with which particular domains were associated with mortality in multivariable analysis was determined. RESULTS Thirty-three studies (28 in hospitalized individuals, five in nursing home residents) reported a large number of characteristics associated with mortality that could be categorized in seven domains: cognitive function, disease diagnosis, laboratory values, nutrition, physical function, pressure ulcers, and shortness of breath. Measures of physical function and nutrition were the domains most frequently associated with mortality up to 1 year from the time of evaluation for hospitalized individuals and nursing home residents; measures of physical function, cognitive function, and nutrition were the domains most frequently associated with in-hospital mortality for hospitalized individuals. CONCLUSION Of a large number of health-related characteristics of older persons shown to be associated with short-term mortality, measures of nutrition, physical function, and cognitive function were the domains of health most frequently associated with mortality. These domains provide easily measurable factors that may serve as helpful markers for individuals at high mortality risk.