A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability

• Published in: Molecular systems biology 2023-07, Vol.19 (7), p.e11267-n/a
• Main Authors: Moretton, Amandine, Kourtis, Savvas, Gañez Zapater, Antoni, Calabrò, Chiara, Espinar Calvo, Maria Lorena, Fontaine, Frédéric, Darai, Evangelia, Abad Cortel, Etna, Block, Samuel, Pascual‐Reguant, Laura, Pardo‐Lorente, Natalia, Ghose, Ritobrata, Vander Heiden, Matthew G, Janic, Ana, Müller, André C, Loizou, Joanna I, Sdelci, Sara
• Format: Article
• Language: English
• Subjects: aspartate metabolism; Aspartic Acid - genetics; Aspartic Acid - metabolism; Availability; Cell cycle; Cell proliferation; Chromatin; CRISPR; Damage accumulation; Damage detection; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; DNA damage response; DNA repair; electron transport chain; EMBO13; EMBO21; Enzymes; Etoposide; Genomes; Humans; Hypoxia; Impact damage; Life Sciences; Metabolism; Metabolites; Metabolomics; Nucleotides; Oxidative Stress - genetics; Peroxiredoxin; Peroxiredoxin 1; Peroxiredoxins - genetics; Peroxiredoxins - metabolism; Proteomics; Reactive oxygen species; Reactive Oxygen Species - metabolism; reactive oxygen species scavenging; Regression analysis; Scavenging; Systems Biology
• ISSN: 1744-4292; 1744-4292
• DOI: 10.15252/msb.202211267

While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential for the resolution of DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Further analysis identified that Peroxiredoxin 1, PRDX1, contributes to the DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it reduces DNA damage‐induced nuclear reactive oxygen species. Moreover, PRDX1 loss lowers aspartate availability, which is required for the DNA damage‐induced upregulation of de novo nucleotide synthesis. In the absence of PRDX1, cells accumulate replication stress and DNA damage, leading to proliferation defects that are exacerbated in the presence of etoposide, thus revealing a role for PRDX1 as a DNA damage surveillance factor. Synopsis Genetic screens, proteomics, and metabolomics are performed to investigate the crosstalk between metabolism and the DNA damage response. Integrative analyses identify Peroxiredoxin‐1 (PRDX1) as a DNA damage surveillance factor. Systematic approaches following DNA damage induction by etoposide reveal the aspects of metabolism that are crucial for maintaining genome integrity. Loss of electron transport chain enzymes is synthetically viable with etoposide, and some of these enzymes are partially located on chromatin 24 h after etoposide release. The metabolic enzyme PRDX1 contributes to DNA repair and translocates to the nucleus where it reduces DNA damage‐induced nuclear ROS. Loss of PRDX1 lowers aspartate availability and perturbs de novo nucleotide synthesis, which induces replication stress and limits the DNA repair capacities of the cells. Graphical Abstract Genetic screens, proteomics, and metabolomics are performed to investigate the crosstalk between metabolism and the DNA damage response. Integrative analyses identify Peroxiredoxin‐1 (PRDX1) as a DNA damage surveillance factor.