p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway
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 DN...
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Published in | Scientific reports Vol. 6; no. 1; p. 38067 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
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30.11.2016
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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. |
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AbstractList | 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. 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. |
ArticleNumber | 38067 |
Author | Fenger, Nick Macdonald, Jeffrey M He, Yizhou Zhang, Yanping Tikunov, Andrey P Franklin, Derek A Leslie, Patrick L |
Author_xml | – sequence: 1 givenname: Derek A surname: Franklin fullname: Franklin, Derek A organization: Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA – sequence: 2 givenname: Yizhou surname: He fullname: He, Yizhou organization: Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA – sequence: 3 givenname: Patrick L surname: Leslie fullname: Leslie, Patrick L organization: Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA – sequence: 4 givenname: Andrey P surname: Tikunov fullname: Tikunov, Andrey P organization: UNC Metabolomics Laboratory, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA – sequence: 5 givenname: Nick surname: Fenger fullname: Fenger, Nick organization: UNC Metabolomics Laboratory, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA – sequence: 6 givenname: Jeffrey M surname: Macdonald fullname: Macdonald, Jeffrey M organization: UNC Metabolomics Laboratory, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA – sequence: 7 givenname: Yanping surname: Zhang fullname: Zhang, Yanping organization: Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu 221002, China |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27901115$$D View this record in MEDLINE/PubMed |
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Snippet | Activation of p53 in response to DNA damage is essential for tumor suppression. Although previous studies have emphasized the importance of p53-dependent cell... Abstract Activation of p53 in response to DNA damage is essential for tumor suppression. Although previous studies have emphasized the importance of... |
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SubjectTerms | Cell cycle Cell Line, Tumor Deoxyribonucleic acid DNA DNA damage DNA Repair Glucose - genetics Glucose - metabolism Humans Kinases Metabolism Nucleosides - biosynthesis Nucleosides - genetics p53 Protein Pentose Phosphate Pathway Phosphofructokinase-2 - genetics Phosphofructokinase-2 - metabolism Signal transduction Tumor suppression Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
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Title | p53 coordinates DNA repair with nucleotide synthesis by suppressing PFKFB3 expression and promoting the pentose phosphate pathway |
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