Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes.

Abstract:

:Driven by oncogenic signaling, glutamine addiction exhibited by cancer cells often leads to severe glutamine depletion in solid tumors. Despite this nutritional environment that tumor cells often experience, the effect of glutamine deficiency on cellular responses to DNA damage and chemotherapeutic treatment remains unclear. Here, we show that glutamine deficiency, through the reduction of alpha-ketoglutarate, inhibits the AlkB homolog (ALKBH) enzymes activity and induces DNA alkylation damage. As a result, glutamine deprivation or glutaminase inhibitor treatment triggers DNA damage accumulation independent of cell death. In addition, low glutamine-induced DNA damage is abolished in ALKBH deficient cells. Importantly, we show that glutaminase inhibitors, 6-Diazo-5-oxo-L-norleucine (DON) or CB-839, hypersensitize cancer cells to alkylating agents both in vitro and in vivo. Together, the crosstalk between glutamine metabolism and the DNA repair pathway identified in this study highlights a potential role of metabolic stress in genomic instability and therapeutic response in cancer.

journal_name

PLoS Biol

journal_title

PLoS biology

authors

Tran TQ,Ishak Gabra MB,Lowman XH,Yang Y,Reid MA,Pan M,O'Connor TR,Kong M

doi

10.1371/journal.pbio.2002810

subject

Has Abstract

pub_date

2017-11-06 00:00:00

pages

e2002810

issue

11

eissn

1544-9173

issn

1545-7885

pii

pbio.2002810

journal_volume

15

pub_type

杂志文章
  • Development, environmental degradation, and disease spread in the Brazilian Amazon.

    abstract::The Amazon is Brazil's greatest natural resource and invaluable to the rest of the world as a buffer against climate change. The recent election of Brazil's president brought disputes over development plans for the region back into the spotlight. Historically, the development model for the Amazon has focused on exploi...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000526

    authors: Castro MC,Baeza A,Codeço CT,Cucunubá ZM,Dal'Asta AP,De Leo GA,Dobson AP,Carrasco-Escobar G,Lana RM,Lowe R,Monteiro AMV,Pascual M,Santos-Vega M

    更新日期:2019-11-15 00:00:00

  • Ionotropic Chemosensory Receptors Mediate the Taste and Smell of Polyamines.

    abstract::The ability to find and consume nutrient-rich diets for successful reproduction and survival is fundamental to animal life. Among the nutrients important for all animals are polyamines, a class of pungent smelling compounds required in numerous cellular and organismic processes. Polyamine deficiency or excess has detr...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1002454

    authors: Hussain A,Zhang M,Üçpunar HK,Svensson T,Quillery E,Gompel N,Ignell R,Grunwald Kadow IC

    更新日期:2016-05-04 00:00:00

  • The slings and arrows of comparative linguistics.

    abstract::In this Formal Comment the authors respond to objections to their previous Essay, reiterating that comparative linguistics is not an easy undertaking. ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000019

    authors: Bolhuis JJ,Beckers GJL,Huybregts MAC,Berwick RC,Everaert MBH

    更新日期:2018-09-24 00:00:00

  • Nucleotide de novo synthesis increases breast cancer stemness and metastasis via cGMP-PKG-MAPK signaling pathway.

    abstract::Metabolic reprogramming to fulfill the biosynthetic and bioenergetic demands of cancer cells has aroused great interest in recent years. However, metabolic reprogramming for cancer metastasis has not been well elucidated. Here, we screened a subpopulation of breast cancer cells with highly metastatic capacity to the l...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000872

    authors: Lv Y,Wang X,Li X,Xu G,Bai Y,Wu J,Piao Y,Shi Y,Xiang R,Wang L

    更新日期:2020-11-13 00:00:00

  • Framing the discussion of microorganisms as a facet of social equity in human health.

    abstract::What do "microbes" have to do with social equity? These microorganisms are integral to our health, that of our natural environment, and even the "health" of the environments we build. The loss, gain, and retention of microorganisms-their flow between humans and the environment-can greatly impact our health. It is well...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000536

    authors: Ishaq SL,Rapp M,Byerly R,McClellan LS,O'Boyle MR,Nykanen A,Fuller PJ,Aas C,Stone JM,Killpatrick S,Uptegrove MM,Vischer A,Wolf H,Smallman F,Eymann H,Narode S,Stapleton E,Cioffi CC,Tavalire HF

    更新日期:2019-11-26 00:00:00

  • Identification of traits and functional connectivity-based neurotraits of chronic pain.

    abstract::Psychological and personality factors, socioeconomic status, and brain properties all contribute to chronic pain but have essentially been studied independently. Here, we administered a broad battery of questionnaires to patients with chronic back pain (CBP) and collected repeated sessions of resting-state functional ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000349

    authors: Vachon-Presseau E,Berger SE,Abdullah TB,Griffith JW,Schnitzer TJ,Apkarian AV

    更新日期:2019-08-20 00:00:00

  • Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon.

    abstract::Several strategies have been pursued to increase the extent of exon 7 inclusion during splicing of SMN2 (survival of motor neuron 2) transcripts, for eventual therapeutic use in spinal muscular atrophy (SMA), a genetic neuromuscular disease. Antisense oligonucleotides (ASOs) that target an exon or its flanking splice ...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0050073

    authors: Hua Y,Vickers TA,Baker BF,Bennett CF,Krainer AR

    更新日期:2007-04-01 00:00:00

  • Group IV phospholipase A(2)alpha controls the formation of inter-cisternal continuities involved in intra-Golgi transport.

    abstract::The organization of intra-Golgi trafficking and the nature of the transport intermediates involved (e.g., vesicles, tubules, or tubular continuities) remain incompletely understood. It was recently shown that successive cisternae in the Golgi stack are interconnected by membrane tubules that form during the arrival of...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1000194

    authors: San Pietro E,Capestrano M,Polishchuk EV,DiPentima A,Trucco A,Zizza P,Mariggiò S,Pulvirenti T,Sallese M,Tete S,Mironov AA,Leslie CC,Corda D,Luini A,Polishchuk RS

    更新日期:2009-09-01 00:00:00

  • Using structural information to change the phosphotransfer specificity of a two-component chemotaxis signalling complex.

    abstract::Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions withi...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1000306

    authors: Bell CH,Porter SL,Strawson A,Stuart DI,Armitage JP

    更新日期:2010-02-09 00:00:00

  • Recombination modulates how selection affects linked sites in Drosophila.

    abstract::One of the most influential observations in molecular evolution has been a strong association between local recombination rate and nucleotide polymorphisms across the genome. This is interpreted as evidence for ubiquitous natural selection. The alternative explanation, that recombination is mutagenic, has been rejecte...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001422

    authors: McGaugh SE,Heil CS,Manzano-Winkler B,Loewe L,Goldstein S,Himmel TL,Noor MA

    更新日期:2012-01-01 00:00:00

  • The Rab5 effector Rabankyrin-5 regulates and coordinates different endocytic mechanisms.

    abstract::The small GTPase Rab5 is a key regulator of clathrin-mediated endocytosis. On early endosomes, within a spatially restricted domain enriched in phosphatydilinositol-3-phosphate [PI(3)P], Rab5 coordinates a complex network of effectors that functionally cooperate in membrane tethering, fusion, and organelle motility. H...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0020261

    authors: Schnatwinkel C,Christoforidis S,Lindsay MR,Uttenweiler-Joseph S,Wilm M,Parton RG,Zerial M

    更新日期:2004-09-01 00:00:00

  • Precise positioning of myosin VI on endocytic vesicles in vivo.

    abstract::Myosin VI has been studied in both a monomeric and a dimeric form in vitro. Because the functional characteristics of the motor are dramatically different for these two forms, it is important to understand whether myosin VI heavy chains are brought together on endocytic vesicles. We have used fluorescence anisotropy m...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0050210

    authors: Altman D,Goswami D,Hasson T,Spudich JA,Mayor S

    更新日期:2007-08-01 00:00:00

  • Role of translational coupling in robustness of bacterial chemotaxis pathway.

    abstract::Chemotaxis allows bacteria to colonize their environment more efficiently and to find optimal growth conditions, and is consequently under strong evolutionary selection. Theoretical and experimental analyses of bacterial chemotaxis suggested that the pathway has been evolutionarily optimized to produce robust output u...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1000171

    authors: Løvdok L,Bentele K,Vladimirov N,Müller A,Pop FS,Lebiedz D,Kollmann M,Sourjik V

    更新日期:2009-08-01 00:00:00

  • Adaptation to Temporally Fluctuating Environments by the Evolution of Maternal Effects.

    abstract::All organisms live in temporally fluctuating environments. Theory predicts that the evolution of deterministic maternal effects (i.e., anticipatory maternal effects or transgenerational phenotypic plasticity) underlies adaptation to environments that fluctuate in a predictably alternating fashion over maternal-offspri...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1002388

    authors: Dey S,Proulx SR,Teotónio H

    更新日期:2016-02-24 00:00:00

  • Hox proteins display a common and ancestral ability to diversify their interaction mode with the PBC class cofactors.

    abstract::Hox transcription factors control a number of developmental processes with the help of the PBC class proteins. In vitro analyses have established that the formation of Hox/PBC complexes relies on a short conserved Hox protein motif called the hexapeptide (HX). This paradigm is at the basis of the vast majority of expe...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001351

    authors: Hudry B,Remacle S,Delfini MC,Rezsohazy R,Graba Y,Merabet S

    更新日期:2012-01-01 00:00:00

  • Serial block-face scanning electron microscopy to reconstruct three-dimensional tissue nanostructure.

    abstract::Three-dimensional (3D) structural information on many length scales is of central importance in biological research. Excellent methods exist to obtain structures of molecules at atomic, organelles at electron microscopic, and tissue at light-microscopic resolution. A gap exists, however, when 3D tissue structure needs...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0020329

    authors: Denk W,Horstmann H

    更新日期:2004-11-01 00:00:00

  • Phase-coding memories in mind.

    abstract::Temporarily holding information in mind is an important part of many cognitive processes, such as reasoning and language. The amount of information that can be actively held "in mind" at any time is greatly limited-research suggests that we can only actively hold three or four pieces of information at once. A central ...

    journal_title:PLoS biology

    pub_type: 评论,杂志文章

    doi:10.1371/journal.pbio.3000012

    authors: Hakim N,Vogel EK

    更新日期:2018-08-29 00:00:00

  • Zinc: A small molecule with a big impact on sperm function.

    abstract::Zinc is an essential mineral, but our understanding of its uses in the body is limited. Capitalizing on approaches available in the model system Caenorhabditis elegans, Zhao and colleagues show that zinc transduces a signal that induces sperm to become motile. This is an enigmatic process because sperm in all sexually...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2006204

    authors: Chu DS

    更新日期:2018-06-07 00:00:00

  • Coordinate gene regulation during hematopoiesis is related to genomic organization.

    abstract::Gene loci are found in nuclear subcompartments that are related to their expression status. For instance, silent genes are often localized to heterochromatin and the nuclear periphery, whereas active genes tend to be found in the nuclear center. Evidence also suggests that chromosomes may be specifically positioned wi...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0050309

    authors: Kosak ST,Scalzo D,Alworth SV,Li F,Palmer S,Enver T,Lee JS,Groudine M

    更新日期:2007-11-01 00:00:00

  • High functional diversity in Mycobacterium tuberculosis driven by genetic drift and human demography.

    abstract::Mycobacterium tuberculosis infects one third of the human world population and kills someone every 15 seconds. For more than a century, scientists and clinicians have been distinguishing between the human- and animal-adapted members of the M. tuberculosis complex (MTBC). However, all human-adapted strains of MTBC have...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.0060311

    authors: Hershberg R,Lipatov M,Small PM,Sheffer H,Niemann S,Homolka S,Roach JC,Kremer K,Petrov DA,Feldman MW,Gagneux S

    更新日期:2008-12-16 00:00:00

  • A new type of Na(+)-driven ATP synthase membrane rotor with a two-carboxylate ion-coupling motif.

    abstract::The anaerobic bacterium Fusobacterium nucleatum uses glutamate decarboxylation to generate a transmembrane gradient of Na⁺. Here, we demonstrate that this ion-motive force is directly coupled to ATP synthesis, via an F₁F₀-ATP synthase with a novel Na⁺ recognition motif, shared by other human pathogens. Molecular model...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001596

    authors: Schulz S,Iglesias-Cans M,Krah A,Yildiz O,Leone V,Matthies D,Cook GM,Faraldo-Gómez JD,Meier T

    更新日期:2013-01-01 00:00:00

  • Generation of functional blood vessels from a single c-kit+ adult vascular endothelial stem cell.

    abstract::In adults, the growth of blood vessels, a process known as angiogenesis, is essential for organ growth and repair. In many disorders including cancer, angiogenesis becomes excessive. The cellular origin of new vascular endothelial cells (ECs) during blood vessel growth in angiogenic situations has remained unknown. He...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001407

    authors: Fang S,Wei J,Pentinmikko N,Leinonen H,Salven P

    更新日期:2012-01-01 00:00:00

  • The velvet family of fungal regulators contains a DNA-binding domain structurally similar to NF-κB.

    abstract::Morphological development of fungi and their combined production of secondary metabolites are both acting in defence and protection. These processes are mainly coordinated by velvet regulators, which contain a yet functionally and structurally uncharacterized velvet domain. Here we demonstrate that the velvet domain o...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1001750

    authors: Ahmed YL,Gerke J,Park HS,Bayram Ö,Neumann P,Ni M,Dickmanns A,Kim SC,Yu JH,Braus GH,Ficner R

    更新日期:2013-12-01 00:00:00

  • mRNA association by aminoacyl tRNA synthetase occurs at a putative anticodon mimic and autoregulates translation in response to tRNA levels.

    abstract::Aminoacyl-tRNA synthetases (aaRSs) are well studied for their role in binding and charging tRNAs with cognate amino acids. Recent RNA interactome studies had suggested that these enzymes can also bind polyadenylated RNAs. Here, we explored the mRNA repertoire bound by several yeast aaRSs. RNA immunoprecipitation (RIP)...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.3000274

    authors: Levi O,Arava Y

    更新日期:2019-05-17 00:00:00

  • Proteolytic Origin of the Soluble Human IL-6R In Vivo and a Decisive Role of N-Glycosylation.

    abstract::Signaling of the cytokine interleukin-6 (IL-6) via its soluble IL-6 receptor (sIL-6R) is responsible for the proinflammatory properties of IL-6 and constitutes an attractive therapeutic target, but how the sIL-6R is generated in vivo remains largely unclear. Here, we use liquid chromatography-mass spectrometry to iden...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2000080

    authors: Riethmueller S,Somasundaram P,Ehlers JC,Hung CW,Flynn CM,Lokau J,Agthe M,Düsterhöft S,Zhu Y,Grötzinger J,Lorenzen I,Koudelka T,Yamamoto K,Pickhinke U,Wichert R,Becker-Pauly C,Rädisch M,Albrecht A,Hessefort M,Stahnke

    更新日期:2017-01-06 00:00:00

  • ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

    abstract::During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to an...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1002330

    authors: Gallego-Ortega D,Ledger A,Roden DL,Law AM,Magenau A,Kikhtyak Z,Cho C,Allerdice SL,Lee HJ,Valdes-Mora F,Herrmann D,Salomon R,Young AI,Lee BY,Sergio CM,Kaplan W,Piggin C,Conway JR,Rabinovich B,Millar EK,Oakes SR,C

    更新日期:2015-12-30 00:00:00

  • Identification of molecular determinants that govern distinct STIM2 activation dynamics.

    abstract::The endoplasmic reticulum (ER) Ca2+ sensors stromal interaction molecule 1 (STIM1) and STIM2, which connect ER Ca2+ depletion with extracellular Ca2+ influx, are crucial for the maintenance of Ca2+ homeostasis in mammalian cells. Despite the recent progress in unraveling the role of STIM2 in Ca2+ signaling, the mechan...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2006898

    authors: Zheng S,Ma G,He L,Zhang T,Li J,Yuan X,Nguyen NT,Huang Y,Zhang X,Gao P,Nwokonko R,Gill DL,Dong H,Zhou Y,Wang Y

    更新日期:2018-11-16 00:00:00

  • Connectivity and systemic resilience of the Great Barrier Reef.

    abstract::Australia's iconic Great Barrier Reef (GBR) continues to suffer from repeated impacts of cyclones, coral bleaching, and outbreaks of the coral-eating crown-of-thorns starfish (COTS), losing much of its coral cover in the process. This raises the question of the ecosystem's systemic resilience and its ability to reboun...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2003355

    authors: Hock K,Wolff NH,Ortiz JC,Condie SA,Anthony KRN,Blackwell PG,Mumby PJ

    更新日期:2017-11-28 00:00:00

  • The DEAD-box Protein Rok1 Orchestrates 40S and 60S Ribosome Assembly by Promoting the Release of Rrp5 from Pre-40S Ribosomes to Allow for 60S Maturation.

    abstract::DEAD-box proteins are ubiquitous regulators of RNA biology. While commonly dubbed "helicases," their activities also include duplex annealing, adenosine triphosphate (ATP)-dependent RNA binding, and RNA-protein complex remodeling. Rok1, an essential DEAD-box protein, and its cofactor Rrp5 are required for ribosome ass...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.1002480

    authors: Khoshnevis S,Askenasy I,Johnson MC,Dattolo MD,Young-Erdos CL,Stroupe ME,Karbstein K

    更新日期:2016-06-09 00:00:00

  • Do plants have a segregated germline?

    abstract::For the last 100 years, it has been uncontroversial to state that the plant germline is set aside late in development, but there is surprisingly little evidence to support this view. In contrast, much evolutionary theory and several recent empirical studies seem to suggest the opposite-that the germlines of some and p...

    journal_title:PLoS biology

    pub_type: 杂志文章

    doi:10.1371/journal.pbio.2005439

    authors: Lanfear R

    更新日期:2018-05-16 00:00:00