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Quantitative subcellular metabolomic measurements can explain the roles of metabolites in cellular processes but are subject to multiple confounding factors. We developed stable isotope labeling of essential nutrients in cell culture-subcellular fractionation (SILEC-SF), which uses isotope-labeled internal standard controls that are present throughout fractionation and processing to quantify acyl-coenzyme A (acyl-CoA) thioesters in subcellular compartments by liquid chromatography-mass spectrometry. We tested SILEC-SF in a range of sample types and examined the compartmentalized responses to oxygen tension, cellular differentiation, and nutrient availability. Application of SILEC-SF to the challenging analysis of the nuclear compartment revealed a nuclear acyl-CoA profile distinct from that of the cytosol, with notable nuclear enrichment of propionyl-CoA. Using isotope tracing, we identified the branched chain amino acid isoleucine as a major metabolic source of nuclear propionyl-CoA and histone propionylation, thus revealing a new mechanism of crosstalk between metabolism and the epigenome., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Nutrient-sensing mechanisms ensure that cellular activities are coordinated with nutrient availability. Recent work has established links between metabolite pools and protein post-translational modifications, as metabolites are substrates of enzymes that add or remove modifications such as acetylation, methylation, and glycosylation. Cancer cells undergo metabolic reprogramming and exhibit metabolic plasticity that allows them to survive and proliferate within the tumor microenvironment. In this article we review the evidence that, in cancer cells, nutrient availability and oncogenic metabolic reprogramming impact the abundance of key metabolites that regulate signaling and epigenetics. We propose models to explain how these metabolites may control locus-specific chromatin modification and gene expression. Finally, we discuss emerging roles of metabolites in regulating malignant phenotypes and tumorigenesis via transcriptional control. An improved understanding of how metabolic alterations in cancer affect nuclear gene regulation could uncover new vulnerabilities to target therapeutically., (Copyright © 2018 Elsevier Inc. All rights reserved.)

While maintaining the integrity of the genome and sustaining bioenergetics are both fundamental functions of the cell, potential crosstalk between metabolic and DNA repair pathways is poorly understood. Since histone acetylation plays important roles in DNA repair and is sensitive to the availability of acetyl coenzyme A (acetyl-CoA), we investigated a role for metabolic regulation of histone acetylation during the DNA damage response. In this study, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455 downstream of ataxia telangiectasia mutated (ATM) and AKT following DNA damage. ACLY facilitates histone acetylation at double-strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repair by homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment. Upon PARP inhibition, ACLY silencing promotes genomic instability and cell death. Thus, the spatial and temporal control of acetyl-CoA production by ACLY participates in the mechanism of DNA repair pathway choice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Nutrient stress is generally considered from the standpoint of how cells detect and respond to an insufficient supply of nutrients to meet their bioenergetic needs. However, cells also experience stress as a result of nutrient excess, during which reactive oxygen species (ROS) production exceeds that required for normal physiological responses. This may occur as a result of oncogene activation or chronic exposure to growth factors combined with high levels of nutrients. As a result, multiple mechanisms have evolved to allow cells to detect and adapt to elevated levels of intracellular metabolites, including promotion of signaling and proliferation by ROS, amino acid-dependent mTOR activation, and regulation of signaling and transcription through metabolite-sensitive protein modifications. We discuss how each of these responses can contribute to the development and/or progression of cancer under conditions of cellular nutrient excess and their potential roles in linking chronic organismal over-nutrition (obesity) with cancer., (Copyright © 2010 Elsevier Inc. All rights reserved.)