title: p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway.
abstract: Activation of p53 in response to DNA damage is essential for tumor suppression. Although previous studies have emphasized the importance of p53-dependent cell cycle arrest and apoptosis for tumor suppression, recent studies have suggested that other areas of p53 regulation, such as metabolism and DNA damage repair (DDR), are also essential for p53-dependent tumor suppression. However, the intrinsic connections between p53-mediated DDR and metabolic regulation remain incompletely understood. Here, we present data suggesting that p53 promotes nucleotide biosynthesis in response to DNA damage by repressing the expression of the phosphofructokinase-2 (PFK2) isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a rate-limiting enzyme that promotes glycolysis. PFKFB3 suppression increases the flux of glucose through the pentose phosphate pathway (PPP) to increase nucleotide production, which results in more efficient DNA damage repair and increased cell survival. Interestingly, although p53-mediated suppression of PFKFB3 could increase the two major PPP products, NADPH and nucleotides, only nucleotide production was essential to promote DDR. By identifying the novel p53 target PFKFB3, we report an important mechanistic connection between p53-regulated metabolism and DDR, both of which play crucial roles in tumor suppression.
authors.affiliation: Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Franklin
authors.affiliation: Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
authors.forename: Yizhou
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Leslie
authors.affiliation: UNC Metabolomics Laboratory, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
authors.forename: Andrey P
authors.initials: AP
authors.lastname: Tikunov
authors.affiliation: UNC Metabolomics Laboratory, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
authors.forename: Nick
authors.initials: N
authors.lastname: Fenger
authors.affiliation: UNC Metabolomics Laboratory, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Macdonald
authors.affiliation: Department of Radiation Oncology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.|Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.|Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.|Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D045744:Cell Line, Tumor; D004260:DNA Repair; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009705:Nucleosides / Q000096:biosynthesis* / Q000235:genetics; D010427:Pentose Phosphate Pathway; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D009705:Nucleosides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D005947:Glucose