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

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 when cells are exposed to 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. Subsequent analysis identified Peroxiredoxin 1, PRDX1, as fundamental for DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it is required to reduce DNA damage-induced nuclear reactive oxygen species levels. Moreover, PRDX1 controls aspartate availability, which is required for the DNA damage repair-induced upregulation of de novo nucleotide synthesis. Loss of PRDX1 leads to an impairment in the clearance of γΗ2ΑΧ nuclear foci, accumulation of replicative stress and cell proliferation defects, thus revealing a crucial role for PRDX1 as a DNA damage surveillance factor.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Bone Marrow

DISEASE(S): Mixed Disorder As Reaction To Stress

SUBMITTER: Frédéric FONTAINE

LAB HEAD: Sara Sdelci

PROVIDER: PXD035532 | Pride | 2023-03-31

REPOSITORIES: pride

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			Action	DRS
	EC_106-M965-A02-P11685-1.raw	Raw
	EC_106-M965-A03-P11686-1.raw	Raw
	EC_106-M965-A05-P11688-1.raw	Raw
	EC_106-M965-A06-P11689-1.raw	Raw
	EC_106-M965-A07-P11690-1.raw	Raw

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

Project description:Targetted metabolomics in U2OS PRDX1 WT and PRDX1-/- 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 when cells are exposed to 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. Subsequent analysis identified Peroxiredoxin 1, PRDX1, as fundamental for DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it is required to reduce DNA damage-induced nuclear reactive oxygen species levels. Moreover, PRDX1 controls aspartate availability, which is required for the DNA damage repair-induced upregulation of de novo nucleotide synthesis. Loss of PRDX1 leads to an impairment in the clearance of γΗ2ΑΧ nuclear foci, accumulation of replicative stress and cell proliferation defects, thus revealing a crucial role for PRDX1 as a DNA damage surveillance factor.

2022-07-19 | ST002234 | MetabolomicsWorkbench

Peroxiredoxin 1 protects telomeres from oxidative damage preserving chromosome ends for extension by telomerase

Project description:With the increase of atmospheric oxygen 2.3 billion years ago, mechanisms evolved to mitigate the toxic effects of oxygen radicals. Telomeres appear particularly susceptible to oxidative damage, which leads to cellular and organismal aging, cancer, cardiac failure and other diseases. Specific mechanisms of telomere protection from oxidative damage and the molecular consequences of the damage have not been described. Here, we identify the antioxidant enzyme peroxiredoxin 1 (PRDX1) enriched in telomeric chromatin in S and G2 phases of the cell cycle during which telomeres become replicated. PRDX1 depletion leads to oxidative damage of telomeric DNA without affecting the bulk of genomic DNA. The oxidized nucleotide 8-oxo-2’deoxyguanosine-5’-triphosphate (8oxodGTP) can be incorporated by telomerase into telomeric repeats but it mediates premature chain termination when incorporated as first G in the telomeric 5’-TTAGGG-3’ sequence. In dependency of the alignment position within the telomerase RNA template, terminus 8oxoG containing DNA substrates also completely block extension by telomerase. We propose two major mechanisms by which PRDX1 counteracts telomere damage and aging. In safeguarding telomeres from oxygen radicals, PRDX1 prevents DNA damage, telomere replication defects and mutations that will perturb recognition of telomeric DNA by shelterin components. In preventing modification of the telomeric DNA substrate and the dNTP pool, PRDX1 preserves telomeres for elongation by telomerase.

2016-12-07 | PXD002626 | Pride

Immunoprecipitation of RNA-DNA hybrid interacting proteins in Trypanosoma brucei reveals conserved and novel activities, including in host immune evasion by antigenic variation

Project description:RNA-DNA hybrids are widespread epigenetic features of genomes that provide a growing range of activities in transcription, chromatin and DNA replication and repair. Understanding of these diverse functions has been advanced by characterising the proteins that interact with the hybrids, with all such studies revealing hundreds of potential interactors. However, all interaction analyses to date have focused on mammalian cells, and so it is unclear if a similar spectrum of RNA-DNA hybrid interactors found in other eukaryotes, thus limiting our understanding of the conserved and lineage-specific activities linked to these genetic structures. The African trypanosome is a compelling organism in which to address these questions. As a divergent single-cell eukaryotic parasite of the Discoba grouping, Trypanosoma brucei displays substantial divergence in several aspects of core biology from its mammalian host and, unusually for a protist, has well-developed tools for molecular genetic analysis. For these reasons, we used DNA-RNA hybrid immunoprecipitation coupled with mass spectrometry to reveal 602 putative interactors in T. brucei mammal- or insect vector-infective stage cells. We show that the approach selects for a subset of the parasite proteome and reveals a range of predicted RNA-DNA hybrid associated activities, some overlapping with similar studies in mammals. We demonstrate that loss of three factors, two putative helicases and a RAD51 paralogue, impact on T. brucei nuclear RNA-DNA hybrid and DNA damage levels. Moreover, loss of each affects the operation of the crucial parasite immune survival mechanism of antigenic variation. Thus, our work reveals the broad range of activities contributed by RNA-DNA hybrids to T. brucei biology, including new functions in host immune evasion as well as many conserved with mammals, and so likely fundamental to eukaryotic genome function.

2024-01-26 | PXD042146 | Pride

A trans-generational epigenetic process defines piRNA biogenesis in Drosophila virilis

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2014-09-01 | E-GEOD-59965 | biostudies-arrayexpress

Host genomic regions susceptible to damage during H. pylori infection

Project description:We identify here host genomic regions that are more likely to be damaged during an infection with the human gastirc pathogen Helicobacter pylori and characterize underlying features of them. By ChIP-seq we obtained global information about the localization of the DNA-damage marker H2AXpS139. We used 20 ng of immunoprecipitated DNA of the human gastric cell line AGS to produce 240 mio sequence reads in total and compared the damage-pattern of 6 h and 19 h infected cells with that of 10 Gy irradiated ones. While the overall levesl of DNA damage wetre similar in terms of broken DNA and accumulation of H2AXpS139, infection-induced damage clearly accumulates towards the ends of chromosomal arms, namely telomere-proximal and close to centromeres, it also enriches mainly in genic and especially in transcribed regions. We show, taht this damage pattern is unique to the infection, occurs also in human non-transformed gastric epithelial cells and shows some correlation with previously identified cancer-related genes. Examination of a DNA-damage induced histone modification from four different conditions.

2015-05-18 | E-GEOD-55699 | biostudies-arrayexpress

DNA double-strand breaks and 3D chromatin conformation (ChIP-chip)

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2021-01-29 | E-MTAB-8793 | biostudies-arrayexpress

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