A map of metabolism in the DNA damage response identifies PRDX1 in nuclear ROS scavenging and aspartate synthesis
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ABSTRACT:
PROVIDER: PRJEB54700 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR9951750.fastq.gz | Fastqsanger.gz | |||
| ERR9951751.fastq.gz | Fastqsanger.gz | |||
| ERR9951752.fastq.gz | Fastqsanger.gz | |||
| ERR9951753.fastq.gz | Fastqsanger.gz | |||
| ERR9951754.fastq.gz | Fastqsanger.gz |
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Project description: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.
2023-03-31 | PXD035532 | Pride
Project description: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.
| S-EPMC10333845 | biostudies-literature
Project description:Macrophages respond to environmental cues in a plastic manner and play a crucial role in host defense, inflammation, and tissue homeostasis. Macrophage activation undergoes metabolic and transcriptomic reprogramming to adapt and tailor an appropriate response, regulating inflammation. Reactive oxygen species (ROS) have been shown to play a pivotal role in macrophage activation. Nevertheless, the detailed molecular mechanism of how initial redox signals direct macrophage activation is not fully elucidated. Here, we uncover an unconventional role for histone acetyltransferase MOF (also known as KAT8) in regulating LPS-induced macrophage activation via modulating the acetylation of peroxiredoxin 1 (PRDX1), an H2O2 scavenger. We demonstrate that PRDX1 is a novel substrate of MOF and identify the major MOF-mediated acetylation site at lysine 197. K197 acetylation of PRDX1 (K197ac PRDX1) is dynamic and reversely regulated by HDAC6 or SIRT2. We observe that this acetylation is readily diminished in the immediate response to LPS. We demonstrate that K197ac PRDX1 fine-tunes its peroxidase activity, leading to the modulation of intracellular ROS levels in early response to LPS stimulation. Moreover, K197ac PRDX1 specifically regulates ERK1/2 phosphorylation, thereby modulating glycolytic metabolism in inflammatory macrophages. Consequently, K197ac PRDX1 tunes the expression and production of the proinflammatory cytokine, IL-6. Taken together, our findings describe a novel signaling module, MOF-PRDX1-ERK, which regulates LPS-induced macrophage activation at the metabolic and transcriptional levels.
2024-12-31 | GSE231941 | GEO
Project description:Programmed cell death plays a vital role in shaping limb morphology in amniotes. BMP signaling has been shown to be essential for inducing interdigital cell death, but its relationship with reactive oxygen species (ROS) production, a known driver of this process, remains unclear. Here, we explore the molecular mechanisms by which BMP signaling regulates ROS production and cell death in the interdigital regions of chicken hindlimbs. To identify the ROS-producing cascade genes regulated by BMP signaling, we performed RNA-Seq of the interdigital region with PBS or Noggin bead implantation in chicken hindlimb buds. Subsequently, we performed RNA-seq of the interdigital region from stage 30 to stage 31 chicken hindlimb buds to analyze temporal expression changes of ROS-related genes during the normal progression of interdigital cell death in chicken hindlimbs. This study provides new insights into the ROS-mediated mechanisms of BMP-driven programmed cell death, highlighting the coordinated regulation of ROS generation and scavenging in limb morphogenesis.
2025-12-08 | GSE279142 | GEO
Project description:Programmed cell death plays a vital role in shaping limb morphology in amniotes. BMP signaling has been shown to be essential for inducing interdigital cell death, but its relationship with reactive oxygen species (ROS) production, a known driver of this process, remains unclear. Here, we explore the molecular mechanisms by which BMP signaling regulates ROS production and cell death in the interdigital regions of chicken hindlimbs. To identify the ROS-producing cascade genes regulated by BMP signaling, we performed RNA-Seq of the interdigital region with PBS or Noggin bead implantation in chicken hindlimb buds. Subsequently, we performed RNA-seq of the interdigital region from stage 30 to stage 31 chicken hindlimb buds to analyze temporal expression changes of ROS-related genes during the normal progression of interdigital cell death in chicken hindlimbs. This study provides new insights into the ROS-mediated mechanisms of BMP-driven programmed cell death, highlighting the coordinated regulation of ROS generation and scavenging in limb morphogenesis.
2025-12-08 | GSE279141 | GEO
Project description:Objective: Peroxiredoxin 1 (PRDX1) is a peroxidase and guards against oxidative stress by scavenging intracellular peroxides, whereas it also has been shown to stimulate inflammatory response by functioning as a chaperone protein. The potential in vivo link between PRDX1’s peroxidase activity and its pro-inflammatory activity remains elusive. Methods: We generated peroxidase-dead PRDX1 variant mice by mutating its peroxidatic cysteine at 52 (Cys52) to serine, here referred to as PRDX1Cys52Ser. Trx-TrxR-NADPH coupled activity assay was applied to evaluate the peroxidase activity of global PRDX in PRDX1Cys52Ser variant mice. PRDX1Cys52Ser mice and their wild-type littermates were subjected to western diet or methionine and choline deficient diet feeding. NASH phenotypes were assessed through different analyses including physiological measurements, immunohistochemical staining, and quantitative PCR (qPCR). RNA sequencing, qPCR and western blotting were used to reveal and validate any changes in the signaling pathways responsible for the altered NASH phenotypes observed between WT and PRDX1Cys52Ser variant mice. Results: PRDX1Cys52Ser variant mice showed impaired global PRDX peroxidase activity and reduced susceptibility to diet-induced NASH and liver fibrosis. Mechanistically, PRDX1 Cys52Ser variant suppressed NF-κB signaling and STAT1 signaling pathways that are known to promote inflammation and NASH. Conclusion: The peroxidatic Cys52 of PRDX1 is required for its pro-inflammatory activity in vivo. This study further suggests that PRDX1 plays dual but opposing roles in NASH
2023-08-11 | GSE240198 | GEO
Project description:Macrophage activation undergoes signal-transduced changes in protein modifications, enabling the coordinated control of transcription and cellular metabolism. However, the role of protein acetylation in signal transduction during macrophage activation remains obscure. Here, we demonstrate that peroxiredoxin 1 (PRDX1), a key regulator of redox signaling, is a novel substrate of the MOF lysine acetyltransferase. Employing a gel based in vitro HAT assay followed by LC-MS, we mapped PRDX1 lysine acetylation sites. PRDX1 K197ac was identified as the most prominent MOF acetylation site. We show that MOF-dependent acetylation of lysine 197 of PRDX1 (PRDX1 K197ac) enhances its peroxidase activity. We find that PRDX1 K197ac is an inflammatory signal-regulated modification, which decreases in mouse macrophages stimulated with bacterial lipopolysaccharides (LPS) but not with IL-4 or IL-10. LPS-induced decrease of PRDX1 K197ac elevates cellular ROS accumulation and augments phosphorylation of ERK1/2 but not p38 or AKT phosphorylation. Concomitantly, diminished PRDX1 K197ac stimulates glycolysis, potentiates H3 serine 28 phosphorylation, and ultimately enhances the production of pro-inflammatory mediators such as IL-6. Collectively, our findings uncover a regulatory role for redox protein acetylation during inflammatory macrophage activation through modulating signal transduction and coordinating metabolic and transcriptional programs.
2024-10-25 | PXD046284 | Pride
Project description:Peroxiredoxin 1 (PRDX1), traditionally known as an intracellular antioxidant enzyme, has emerged as a regulator of inflammatory responses via Toll-like receptor 4 (TLR4) signaling. Despite this, the mechanistic details of the PRDX1-TLR4 axis and its impact on osteoclast differentiation remain elusive. Here, we show that PRDX1 suppresses RANKL-induced osteoclast differentiation. Utilizing pharmacological inhibitors, we reveal that PRDX1 inhibits osteoclastogenesis through both TLR4/TRIF and TLR4/MyD88 pathways. Transcriptome analysis revealed PRDX1-mediated alterations in gene expression, particularly upregulating serum amyloid A3 (SAA3) and aconitate decarboxylase 1 (ACOD1), known inhibitors of osteoclast differentiation. Mechanistically, PRDX1-TLR4 signaling activates p65, promoting SAA3 and ACOD1 expression while inhibiting NFATc1, a master regulator of osteoclastogenesis. Remarkably, PRDX1 redirects p65 binding from NFATc1 to SAA3/ACOD1 promoters, thereby suppressing osteoclast formation. Structural analysis showed that monomeric variants of PRDX1 with enhanced TLR4 binding exhibit potent inhibition of osteoclast differentiation. Our findings elucidate the inhibitory role of PRDX1-TLR4 axis in osteoclastogenesis, providing insights into therapeutic strategies for bone-related disorders.
2024-11-12 | GSE267039 | GEO
Project description:The regulation of metabolites comprises the fundamental biological processes of human. More new phenotypes of classic metabolites were revealed, while the devolution of functional targets and mechanisms of them still have many gaps due to diversity in structures and functions. Here, we report a bioinformation and attention mechanism based deep learning model leveraging abundant bioinformation of metabolites for functional target prediction of specific phenotypes. Taking advantage of this model, the potential target database of 3,382 common human metabolites were resourced publicly. Norepinephrine was identified as a selective peroxidase inhibitor of peroxiredoxin 1 (PRDX1) for atherosclerosis aggravation in model validation experiments. Salvianolic acid A (SAA) was screened out as PRDX1 exogenous stabilization compound for rescuing norepinephrine’s aggravation effects in vivo. Besides, bulk RNA-Sequencing analysis indicated norepinephrine aggravates atherosclerosis through activating transcriptional activity of SREBP2 in a ROS dependent manner. Overall, our research provides a new computational regime for metabolites target identification besides experimental chemical proteomics and PRDX1 stabilization was validated a potential druggable target for cardiovascular diseases intervention.
2025-05-07 | GSE282003 | GEO
Project description: Not available
| ST002234 | MetabolomicsWorkbench