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

ABSTRACT: 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.

ORGANISM(S): Human Homo Sapiens

TISSUE(S): Cultured Cells

DISEASE(S): Dna Damage Response

SUBMITTER: Savvas Kourtis

PROVIDER: ST002234 | MetabolomicsWorkbench | Tue Jul 19 00:00:00 BST 2022

REPOSITORIES: MetabolomicsWorkbench

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Similar Datasets

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

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

Nuclear poly(A)-binding protein 1 is an ATM target and essential for DNA double-strand break rep

Project description:The DNA damage response (DDR) is an extensive signaling network that is robustly mobilized by DNA double-strand breaks (DSBs). The primary transducer of the DSB response is the protein kinase, ataxia-telangiectasia, mutated (ATM). Here, we establish nuclear poly(A)-binding protein 1 (PABPN1) as a novel target of ATM and a crucial player in the DSB response. PABPN1 usually functions in regulation of RNA processing and stability. We establish that PABPN1 is recruited to the DDR as a critical regulator of DSB repair. A portion of PABPN1 relocalizes to DSB sites and is phosphorylated on Ser95 in an ATM-dependent manner. PABPN1 depletion sensitizes cells to DSBinducing agents and prolongs the DSB-induced G2/M cell-cycle arrest, and DSB repair is hampered by PABPN1 depletion or elimination of its phosphorylation site. PABPN1 is required for optimal DSB repair via both nonhomologous end-joining (NHEJ) and homologous recombination repair (HRR), and specifically is essential for efficient DNAend resection, an initial, key step in HRR. Using mass spectrometry analysis, we capture DNA damage-induced interactions of phospho-PABPN1, including well-established DDR players as well as other RNA metabolizing proteins. Our results uncover a novel ATM-dependent axis in the rapidly growing interface between RNA metabolism and the DDR.

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The 26S proteasome substrates and the dynamics of nuclear proteome upon DNA damage

Project description:Upon DNA damage, numerous proteins are targeted for ubiquitin-dependent proteasomal degradation. We show that phosphorylation of Rpn10/PSMD4 (ubiquitin receptor of the proteasome) at Ser266, is required for DNA repair. Here, we performed TurboID proximity labeling for capturing the proteasome substrates under DNA damage. Numerous proteins which involve in DNA damage response, chromosome reorganization cell cycle and histone modification were identified as the potential pronuteasome substrates. We find that DNA damage reduced the overall affinity between substrates and wild-type Rpn10 compared to Rpn10-Ser266 mutant cells. Combining TMT quantitative proteomic studies, we observed the dynamics of more than 2,000 nuclear proteins upon DNA damage and time course release. Most proteins were accumulated in wild-type cells in the time course release, while the Rpn10-Ser266 mutant cells show almost no changes in protein level. These findings reveal an inherent self-limiting mechanism of the proteasome that, by controlling substrate recognition through Rpn10 phosphorylation, fine-tunes protein degradation for optimal responses under stress.

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Nuclear phosphorylated Dicer processes double-stranded RNA in response to DNA damage

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Dose dependent transcriptional response to ionizing radiation is orchestrated with DNA repair within the nuclear space [RNA-seq]

Project description:Radiation therapy is commonly used to treat glioblastoma multiforme (GBM) brain tumor. Ionizing radiation (IR) induces dose- specific variations in transcriptional programs, implicating they are tightly regulated and critical components in the tumor response and survival. Yet, our understanding of the downstream molecular events triggered by lethal vs sublethal IR doses is limited. Herein, we report that variations in the genetic programs are positively and functionally correlated with the exposure to lethal or sublethal IR doses. Genome architecture analysis revealed that gene regulation is spatially and temporally coordinated with DNA repair kinetics. Radiation-activated genes were pre-positioned in active sub-nuclear compartments and were up-regulated following DNA damage response, while the DNA repair activity shifted to the inactive heterochromatic spatial compartments. The IR dose affected the levels of DNA damage repair and transcription modulation, but not the order of events, which was linked to their spatial nuclear positioning. Thus, distinct coordinated temporal dynamics of DNA damage repair and transcription reprogramming in the active and inactive sub-nuclear compartments highlight the importance of high-order genome organization in synchronizing the molecular events following IR.

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Dose dependent transcriptional response to ionizing radiation is orchestrated with DNA repair within the nuclear space [4C-seq]

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Rif1 S-acylation mediates DNA double-strand break repair at the inner nuclear membrane

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2017-03-31 | MSV000080853 | MassIVE

Nuclear phosphatidylinositol-5-phosphate regulates ING2 stability at discrete chromatin targets in response to DNA damage [expression]

Project description:ING2 (inhibitor of growth family member 2) is a component of a chromatin-regulatory complex that represses gene expression and is implicated in cellular processes that promote tumor suppression. However, few direct genomic targets of ING2 have been identified and the mechanism(s) by which ING2 selectively regulates genes remains unknown. Here we provide evidence that direct association of ING2 with the nuclear phosphoinositide phosphatidylinositol-5-phosphate (PtdIns(5)P) regulates a subset of ING2 targets in response to DNA damage. At these target genes, the binding event between ING2 and PtdIns(5)P is required for ING2 promoter occupancy and ING2-associated gene repression. Moreover, depletion of PtdIns(5)P attenuates ING2-mediated regulation of these targets in the presence of DNA damage. Taken together, these findings support a model in which PtdIns(5)P functions as a sub-nuclear trafficking factor that stabilizes ING2 at discrete genomic sites. Genome-wide expression profiling of HT1080 cells stably transduced with ING2 or a ING2 lipid binding mutant in the presence of vehicle (DMSO) or etoposide. Each condition is tested in triplicate

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