Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

MTORC1-Driven DDA1 Phosphorylation Promotes DNA Repair and Glioblastoma Progression

ABSTRACT: DDA1 is a protein involved in protein degradation, cell cycle regulation, and DNA damage repair. Interestingly, recent studies have revealed its differential expression across various tumor types. However, how DDA1 functions as a tumorogenic factor remains to be elucidated. Through studies in multiple glioblastoma cell models, we identified a physical association between cytoplasmic DDA1 and Raptor, a key component of lysosome-associated mTORC1. We report that amino acid stimulation triggers phosphorylation of DDA1 at serine 33, promoting its nuclear translocation and involvement in DNA damage repair. Integrated genomic and transcriptomic analyses revealed that the mTORC1-DDA1S33-DNA repair axis regulates the expression of a subset of metabolic genes, including ENO2, a glycolytic enzyme; CA12, which contributes to intracellular and extracellular pH homeostasis; and NMRK1, a key enzyme in nicotinamide riboside metabolism. Notably, DDA1 deficiency markedly impaired glioblastoma growth and triggered a compensatory upregulation of metabolic activity to sustain tumor cell survival. These metabolic genes likely supply essential nutrients required for effective DNA repair. Our findings establish DDA1 as a previously unrecognized phosphorylation target downstream of mTORC1, serving as a critical mediator of mTORC1-driven DNA damage response and a key regulator of glioblastoma progression, thereby expanding our understanding of gliomagenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303079 | GEO | 2025/07/29

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Accumulating DNA damage and insufficient DNA repair in senescent cells underlie persistent DNA damage signaling

Project description:Senescent cells are a major cause of organismal aging and a key target for anti-aging therapies. Persistent DNA damage signaling is a primary driver of the induction and maintenance of cellular senescence. However, many DNA damaging stimuli that induce senescence, such as irradiation or transient exposure to genotoxic drugs, are transient. The mechanisms underlying persistent damage signaling in senescent cells, and why senescent cells fail to repair damaged DNA, remain unknown. Here, we were able to assess the mechanisms underlying persistence of DNA damage and senescence maintenance by designing a precisely controllable senescence system that does not require potent stressors to induce senescence. We demonstrate that sustained mTORC1 signaling in senescent cells causes gradually accumulating DNA damage and an inflammatory response that maintains cell-cycle arrest. Markedly, activation of E2F transcription, which promotes expression of DNA repair proteins, can reverse accumulated DNA damage. Thus, persistent DNA damage signaling arises in senescent cells by uncoupling of mTORC1 and E2F signaling, whereby prolonged mTORC1 activity causes gradually increasing DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.

2023-06-01 | GSE153683 | GEO

Phosphoproteomic Analysis Defines BABAM1 as mTORC2 Downstream Effector Promoting DNA Damage Response in Glioblastoma Cells

Project description:Glioblastoma (GBM) is a devastating primary brain cancer with a poor prognosis. GBM is associated with an abnormal mechanistic target of rapamycin (mTOR) signaling pathway, consisting of two distinct kinase complexes: mTORC1 and mTORC2. The complexes play critical roles in cell proliferation, survival, migration, metabolism, and DNA damage response. This study investigated the aberrant mTORC2 signaling pathway in GBM cells by performing quantitative phosphoproteomic analysis of U87MG cells under different drug treatment conditions. Interestingly, a functional analysis of phosphoproteome revealed that mTORC2 inhibition might be involved in double-strand break (DSB) repair. We further characterized the relationship between mTORC2 and BRISC and BRCA1-A Complex Member 1 (BABAM1). We demonstrated that pBABAM1 at Ser29 is regulated by mTORC2 to initiate DNA damage response, contributing to DNA repair and cancer cell survival. Accordingly, the inactivation of mTORC2 significantly ablated pBABAM1 (Ser29), reduced DNA repair activities in the nucleus, and promoted apoptosis of the cancer cells. Furthermore, we also recognized that histone H2AX phosphorylation at Ser139 (γH2AX) could be controlled by mTORC2 to repair the DNA. These results provided a better understanding of mTORC2 function in oncogenic DNA damage response and might lead to specific mTORC2 treatments for brain cancer patients in the future.

2022-11-08 | PXD033325 | Pride

mTORC1-Driven DDA1 Phosphorylation Promotes DNA Repair and Glioblastoma Progression

Project description:mTORC1-Driven DDA1 Phosphorylation Promotes DNA Repair and Glioblastoma Progression

| PRJNA1293952 | ENA

Identification of DHC2 associated nuclear proteins in DHC2 knockdown U87 cells

Project description:The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by MGMT. However, many MGMT-negative glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DHC2 was highly expressed in MGMT-negative recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT-negative glioblastoma patients. In vivo and in vitro, silencing DHC2 enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-negative glioblastoma cells. It is known DHC2 is related to intracellular cargo transportation. To identify the potential interacted “cargo” DHC2 transported and explore the underlying molecular mechanisms of DHC2-midiated DNA damage repair, we performed subcellular proteomic and bioinformatic analyses.

2022-02-28 | PXD012032 | Pride

Inhibition of nuclear PTEN tyrosine phosphorylation enhances glioma radiation sensitivity through attenuated DNA repair

Project description:Glioblastoma (GBM) is the most lethal brain tumour that occurs in adults and treatment for GBM has been largely unsuccessful. Ionizing radiation (IR) and chemotherapeutic agents are employed as standard of care treatment for GBM patients and both result in DNA damage. Previous data identified phosphorylation of PTEN at tyrosine 240 (pY240) in samples from patients with recurrent GBM receiving standard of care treatment and was associated with decreased overall survival. Here we demonstrate that pY240 PTEN that was triggered by FGFR2 signaling, enhanced DNA repair by facilitating the loading of PTEN onto chromatin through its interaction with KI-67 and subsequent recruitment of the DNA repair protein, RAD51, to sites of DNA damage. Thus, tumour cells with pY240 PTEN are efficient at repairing DNA damage which would be predicted to result in resistance to therapy. These findings suggest the FGFR-pY240 PTEN-DNA repair mechanism as a therapeutic target for enhancing GBM therapy.

2017-08-07 | MSV000081423 | MassIVE

ATR promotes mTORC1 activity via de novo cholesterol synthesis

Project description:DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback mechanisms. Key mediators of the DNA damage response and cellular metabolic regulation include Ataxia Telangiectasia and Rad3-related protein (ATR) and the mechanistic Target of Rapamycin Complex 1 (mTORC1), respectively. Previous studies have established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms by which mTORC1 is activated in this context remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. Here, we demonstrate that ATR promotes mTORC1 activity across various cellular models under basal conditions. This effect is particularly enhanced in cells following the loss of p16, which we have previously associated with hyperactivation of mTORC1 signaling and here found increased ATR activity. Mechanistically, we found that ATR promotes de novo cholesterol synthesis and mTORC1 activation through the upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Furthermore, the attenuation of mTORC1 activity resulting from ATR inhibition was rescued by supplementation with lanosterol or cholesterol in multiple cellular con-texts. This restoration corresponded with enhanced localization of mTOR to the lysosome. Collectively, our findings link ATR and mTORC1 signaling through the modulation of cholesterol metabolism.

2025-04-01 | PXD061265 | Pride

Loss of genome maintenance is linked to mTORC1 signaling and accelerates podocyte damage

Project description:DNA repair is essential for preserving genome integrity. Podocytes, post-mitotic epithelial cells of the kidney filtration unit, bear limited regenerative capacity, yet their survival is indispensable for kidney health. Podocyte loss is a hallmark of the aging process and of many diseases, but the underlying factors remain unclear. We investigated the consequences of DNA damage in a podocyte-specific knockout mouse model for Ercc1 and in cultured podocytes under genomic stress. Furthermore, we characterized DNA damage-related alterations in mouse and human renal tissue of different ages and patients suffering from minimal change disease and focal segmental glomerulosclerosis. Ercc1 knockout resulted in accumulation of DNA damage ensuing albuminuria and kidney disease. Podocytes reacted to genomic stress by activating mTORC1 signaling in vitro and in vivo. Perturbed DNA repair gene expression and genomic stress in podocytes was also detected in focal segmental glomerulosclerosis. Beyond that, DNA damage signaling occurred in podocytes of healthy aging mice and humans. We provide evidence that genome maintenance in podocytes is linked to the mTORC1 pathway, involved in the aging process and the development of glomerulosclerosis.

2025-05-22 | GSE292420 | GEO

Exploring the impact of chonic hypoxia on the expression of DNA repair gene in Glioblastoma and Medulloblastoma cells.

Project description:Hypoxia is known to impact DNA repair mechanisms. The primary aim of this study was to examine the impact of chronic (5 days) hypoxia on the expression of DNA repair genes in glioblastoma and medulloblastoma cell lines. The NanoString nCounter VantageTM RNA Panel for DNA Damage and Repair (LBL-10250-03) was utilised to analyse gene expression using total RNA extracted from cells.

2019-10-23 | GSE139250 | GEO

Homo sapiens

Project description:3alpha-acetonyltabersonine induces glioblastoma apoptosis via the inhibition of DNA damage repair

| PRJNA376875 | ENA

Metabolic responses induced by DNA damage and poly (ADP-ribose) polymerase (PARP) inhibition in MCF-7 cells

Project description:Genomic instability is one of the hallmarks of cancer. Several chemotherapeutic drugs and radiotherapy induce DNA damage to prevent cancer cell replication. Cells in turn activate different DNA damage response (DDR) pathways to either repair the damage or induce cell death. These DDR pathways also elicit metabolic alterations which can play a significant role in the proper functioning of the cells. The understanding of these metabolic effects resulting from different types of DNA damage and repair mechanisms is currently lacking. In this study, we used NMR metabolomics to identify metabolic pathways which are altered in response to different DNA damaging agents. By comparing the metabolic responses in MCF-7 cells, we identified the activation of poly (ADP-ribose) polymerase (PARP) in methyl methanesulfonate (MMS)-induced DNA damage. PARP activation led to a significant depletion of NAD+. PARP inhibition using veliparib (ABT-888) was able to successfully restore the NAD+ levels in MMS-treated cells. In addition, double strand break induction by MMS and veliparib exhibited similar metabolic responses as zeocin, suggesting an application of metabolomics to classify the types of DNA damage responses. This prediction was validated by studying the metabolic responses elicited by radiation. Our findings indicate that cancer cell metabolic responses depend on the type of DNA damage responses and can also be used to classify the type of DNA damage.

2015-08-01 | MTBLS177 | MetaboLights

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data