title: Aspartate Rescues S-phase Arrest Caused by Suppression of Glutamine Utilization in KRas-driven Cancer Cells.
abstract: During G1-phase of the cell cycle, normal cells respond first to growth factors that indicate that it is appropriate to divide and then later in G1 to the presence of nutrients that indicate sufficient raw material to generate two daughter cells. Dividing cells rely on the "conditionally essential" amino acid glutamine (Q) as an anaplerotic carbon source for TCA cycle intermediates and as a nitrogen source for nucleotide biosynthesis. We previously reported that while non-transformed cells arrest in the latter portion of G1 upon Q deprivation, mutant KRas-driven cancer cells bypass the G1 checkpoint, and instead, arrest in S-phase. In this study, we report that the arrest of KRas-driven cancer cells in S-phase upon Q deprivation is due to the lack of deoxynucleotides needed for DNA synthesis. The lack of deoxynucleotides causes replicative stress leading to activation of the ataxia telangiectasia and Rad3-related protein (ATR)-mediated DNA damage pathway, which arrests cells in S-phase. The key metabolite generated from Q utilization was aspartate, which is generated from a transaminase reaction whereby Q-derived glutamate is converted to α-ketoglutarate with the concomitant conversion of oxaloacetate to aspartate. Aspartate is a critical metabolite for both purine and pyrimidine nucleotide biosynthesis. This study identifies the molecular basis for the S-phase arrest caused by Q deprivation in KRas-driven cancer cells that arrest in S-phase in response to Q deprivation. Given that arresting cells in S-phase sensitizes cells to apoptotic insult, this study suggests novel therapeutic approaches to KRas-driven cancers.
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065, Biochemistry Program and.
authors.forename: Deven
authors.initials: D
authors.lastname: Patel
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065, Biochemistry Program and.
authors.forename: Deepak
authors.initials: D
authors.lastname: Menon
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065, Biochemistry Program and.
authors.forename: Elyssa
authors.initials: E
authors.lastname: Bernfeld
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065.
authors.forename: Victoria
authors.initials: V
authors.lastname: Mroz
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065, Biology Program, Graduate Center of the City University of New York, New York, New York 10016, and.
authors.forename: Sampada
authors.initials: S
authors.lastname: Kalan
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065, Biochemistry Program and Biology Program, Graduate Center of the City University of New York, New York, New York 10016, and.
authors.forename: Diego
authors.initials: D
authors.lastname: Loayza
authors.affiliation: From the Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10065, Biochemistry Program and Biology Program, Graduate Center of the City University of New York, New York, New York 10016, and Department of Pharmacology, Weill Cornell College of Medicine, New York, New York 10021 foster@genectr.hunter.cuny.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Foster
mesh_terms: D001224:Aspartic Acid / Q000235:genetics / Q000378:metabolism*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002952:Citric Acid Cycle; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D011685:Purine Nucleotides / Q000096:biosynthesis / Q000235:genetics; D011742:Pyrimidine Nucleotides / Q000096:biosynthesis / Q000235:genetics; D059807:S Phase Cell Cycle Checkpoints
chemical_list: C117307:KRAS protein, human; D011685:Purine Nucleotides; D011742:Pyrimidine Nucleotides; D001224:Aspartic Acid; D018698:Glutamic Acid; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D016283:Proto-Oncogene Proteins p21(ras)
keywords: ATR; GTPase Kras (KRAS); KRas; S-Phase arrest; aspartate (aspartic acid); cell cycle; glutamine; nucleotide