2. Academic Validation
  3. A metabolic map of the DNA damage response identifies PRDX1 in the control of nuclear ROS scavenging and aspartate availability

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

  • Mol Syst Biol. 2023 Jun 1;e11267. doi: 10.15252/msb.202211267.
Amandine Moretton # 1 2,  Savvas Kourtis # 3,  Antoni Gañez Zapater # 3,  Chiara Calabrò # 1,  Maria Lorena Espinar Calvo 3,  Frédéric Fontaine 2,  Evangelia Darai 3,  Etna Abad Cortel 4,  Samuel Block 5,  Laura Pascual-Reguant 3,  Natalia Pardo-Lorente 3,  Ritobrata Ghose 3,  Matthew G Vander Heiden 5 6 7,  Ana Janic 4,  André C Müller 2,  Joanna I Loizou 1 2,  Sara Sdelci 3
Affiliations

Affiliations

  • 1 Center for Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
  • 2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 3 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
  • 4 Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
  • 5 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 6 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 7 Dana-Farber Cancer Institute, Boston, MA, USA.
  • # Contributed equally.
PMID: 37259925 DOI: 10.15252/msb.202211267
Abstract

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.

Keywords

DNA damage response; Peroxiredoxin 1; aspartate metabolism; electron transport chain; reactive oxygen species scavenging.

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