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Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity
Nucleotide synthesis is a metabolically demanding process essential for DNA replication and other processes in the cell. Several anticancer drugs that inhibit nucleotide metabolism induce apoptosis. How inhibition of nucleotide metabolism impacts non-apoptotic cell death is less clear. Here, we repo...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Life Science Alliance LLC
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807879/ https://www.ncbi.nlm.nih.gov/pubmed/35074928 http://dx.doi.org/10.26508/lsa.202101157 |
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author | Tarangelo, Amy Rodencal, Jason Kim, Joon Tae Magtanong, Leslie Long, Jonathan Z Dixon, Scott J |
author_facet | Tarangelo, Amy Rodencal, Jason Kim, Joon Tae Magtanong, Leslie Long, Jonathan Z Dixon, Scott J |
author_sort | Tarangelo, Amy |
collection | PubMed |
description | Nucleotide synthesis is a metabolically demanding process essential for DNA replication and other processes in the cell. Several anticancer drugs that inhibit nucleotide metabolism induce apoptosis. How inhibition of nucleotide metabolism impacts non-apoptotic cell death is less clear. Here, we report that inhibition of nucleotide metabolism by the p53 pathway is sufficient to suppress the non-apoptotic cell death process of ferroptosis. Mechanistically, stabilization of wild-type p53 and induction of the p53 target gene CDKN1A (p21) leads to decreased expression of the ribonucleotide reductase (RNR) subunits RRM1 and RRM2. RNR is the rate-limiting enzyme of de novo nucleotide synthesis that reduces ribonucleotides to deoxyribonucleotides in a glutathione-dependent manner. Direct inhibition of RNR results in conservation of intracellular glutathione, limiting the accumulation of toxic lipid peroxides and preventing the onset of ferroptosis in response to cystine deprivation. These results support a mechanism linking p53-dependent regulation of nucleotide metabolism to non-apoptotic cell death. |
format | Online Article Text |
id | pubmed-8807879 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Life Science Alliance LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-88078792022-02-15 Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity Tarangelo, Amy Rodencal, Jason Kim, Joon Tae Magtanong, Leslie Long, Jonathan Z Dixon, Scott J Life Sci Alliance Research Articles Nucleotide synthesis is a metabolically demanding process essential for DNA replication and other processes in the cell. Several anticancer drugs that inhibit nucleotide metabolism induce apoptosis. How inhibition of nucleotide metabolism impacts non-apoptotic cell death is less clear. Here, we report that inhibition of nucleotide metabolism by the p53 pathway is sufficient to suppress the non-apoptotic cell death process of ferroptosis. Mechanistically, stabilization of wild-type p53 and induction of the p53 target gene CDKN1A (p21) leads to decreased expression of the ribonucleotide reductase (RNR) subunits RRM1 and RRM2. RNR is the rate-limiting enzyme of de novo nucleotide synthesis that reduces ribonucleotides to deoxyribonucleotides in a glutathione-dependent manner. Direct inhibition of RNR results in conservation of intracellular glutathione, limiting the accumulation of toxic lipid peroxides and preventing the onset of ferroptosis in response to cystine deprivation. These results support a mechanism linking p53-dependent regulation of nucleotide metabolism to non-apoptotic cell death. Life Science Alliance LLC 2022-01-24 /pmc/articles/PMC8807879/ /pubmed/35074928 http://dx.doi.org/10.26508/lsa.202101157 Text en © 2022 Tarangelo et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Articles Tarangelo, Amy Rodencal, Jason Kim, Joon Tae Magtanong, Leslie Long, Jonathan Z Dixon, Scott J Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity |
title | Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity |
title_full | Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity |
title_fullStr | Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity |
title_full_unstemmed | Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity |
title_short | Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity |
title_sort | nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8807879/ https://www.ncbi.nlm.nih.gov/pubmed/35074928 http://dx.doi.org/10.26508/lsa.202101157 |
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