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      Polyamine catabolism and oxidative damage

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      Journal of Biological Chemistry
      American Society for Biochemistry & Molecular Biology (ASBMB)

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          Abstract

          <p class="first" id="d555978e169">Polyamines (PAs) are indispensable polycations ubiquitous to all living cells. Among their many critical functions, PAs contribute to the oxidative balance of the cell. Beginning with studies by the Tabor laboratory in bacteria and yeast, the requirement for PAs as protectors against oxygen radical–mediated damage has been well established in many organisms, including mammals. However, PAs also serve as substrates for oxidation reactions that produce hydrogen peroxide (H <sub>2</sub>O <sub>2</sub>) both intra- and extracellularly. As intracellular concentrations of PAs can reach millimolar concentrations, the H <sub>2</sub>O <sub>2</sub> amounts produced through their catabolism, coupled with a reduction in protective PAs, are sufficient to cause the oxidative damage associated with many pathologies, including cancer. Thus, the maintenance of intracellular polyamine homeostasis may ultimately contribute to the maintenance of oxidative homeostasis. Again, pioneering studies by Tabor and colleagues led the way in first identifying spermine oxidase in <i>Saccharomyces cerevisiae.</i> They also first purified the extracellular bovine serum amine oxidase and elucidated the products of its oxidation of primary amine groups of PAs when included in culture medium. These investigations formed the foundation for many polyamine-related studies and experimental procedures still performed today. This Minireview will summarize key innovative studies regarding PAs and oxidative damage, starting with those from the Tabor laboratory and including the most recent advances, with a focus on mammalian systems. </p>

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          Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses.

          Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N(1)-acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPR-cas9-mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.
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            Spermidine in health and disease

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              Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG Islands.

              Cancer cells simultaneously harbor global losses and gains in DNA methylation. We demonstrate that inducing cellular oxidative stress by hydrogen peroxide treatment recruits DNA methyltransferase 1 (DNMT1) to damaged chromatin. DNMT1 becomes part of a complex(es) containing DNMT3B and members of the polycomb repressive complex 4. Hydrogen peroxide treatment causes relocalization of these proteins from non-GC-rich to GC-rich areas. Key components are similarly enriched at gene promoters in an in vivo colitis model. Although high-expression genes enriched for members of the complex have histone mark and nascent transcription changes, CpG island-containing low-expression genes gain promoter DNA methylation. Thus, oxidative damage induces formation and relocalization of a silencing complex that may explain cancer-specific aberrant DNA methylation and transcriptional silencing. 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal of Biological Chemistry
                J. Biol. Chem.
                American Society for Biochemistry & Molecular Biology (ASBMB)
                0021-9258
                1083-351X
                November 30 2018
                November 30 2018
                November 30 2018
                October 17 2018
                : 293
                : 48
                : 18736-18745
                Article
                10.1074/jbc.TM118.003337
                6290137
                30333229
                bbe95891-f45c-4a59-a1f5-8b3211b6e251
                © 2018
                History

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