Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

LARP7 is a substrate of BRCA1 that regulats genome instability and tumorigenesis

ABSTRACT: Impaired DNA repair leads to cancer, aging and many genetic diseases. However, understanding of the complexity of DNA is far from complete, resulting in the failure of therapies using genotoxic reagents. Here, we found that LARP7, an RNA-binding protein known to stabilize 7SK RNA, was degraded after DNA injury caused by ionizing radiation and chemotherapy. The LARP7 degradation was catalyzed by an E3 ligase complex of BRCA1 and BARD1 that was triggered by ATM-mediated phosphorylation. LARP7 depletion caused transcriptional repression of the cell cycle regulators CCNB1, CCNB2 and CDK1; this repression arrested cells before the G2/M DNA damage checkpoint and reduced BRCA2 phosphorylation, therefore enhancing Rad51 recruitment and ultimately ensuring the homologous repair of damaged DNA. Importantly, the increased DNA damage repair capacity induced by LARP7 depletion caused resistance to ionizing radiation and CDDP treatment in both wild-type and BRCA1-mutant breast cancer cells and in mouse xenografts. Such resistance also contributed to reduced relapse-free survival rates in breast cancer patients with low levels of LARP7 after chemotherapy. Taken together, the results of this study show that LARP7 coordinates cell cycle progression and faithful DNA repair. We suggest that this mechanism could be exploited to prevent tumorigenesis and improve the effectiveness of cancer therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124393 | GEO | 2019/01/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Radiation-induced epigenetic DNA methylation modification of radiation-response pathways

Project description:Treatment of tumors with ionizing radiation for cancer therapy induces biological responses that include changes in cell cycle, activation of DNA repair mechanisms, and induction of apoptosis or senescence programs. What is not known is whether ionizing radiation induces an epigenetic DNA methylation response or whether epigenetic changes occur in genes in pathways classically associated with the radiation response. We exposed breast cancer cells to 0, 2, or 6 Gy and determined global DNA methylation at 1, 2, 4, 8, 24, 48, and 72 hours post-irradiation. We found that radiation treatment resulted in a DNA methylation response and that cell cycle, DNA repair, and apoptosis pathways were enriched in genes are were differentially-methylated. DNA methylation profiling of ionizing radiation treated cells using the Infinium HumanMethylation450 BeadChip.

2013-07-01 | E-GEOD-45958 | biostudies-arrayexpress

Ma2005-digital response of p53 to DNA damage-ATM Activation Module

Project description:Recent observations show that the single-cell response of p53 to ionizing radiation (IR) is “digital” in that it is the number of oscillations rather than the amplitude of p53 that shows dependence on the radiation dose. We present a model of this phenomenon. In our model, double-strand break (DSB) sites induced by IR interact with a limiting pool of DNA repair proteins, forming DSB–protein complexes at DNA damage foci. The persisting complexes are sensed by ataxia telangiectasia mutated (ATM), a protein kinase that activates p53 once it is phosphorylated by DNA damage. The ATM-sensing module switches on or off the downstream p53 oscillator, consisting of a feedback loop formed by p53 and its negative regulator, Mdm2. In agreement with experiments, our simulations show that by assuming stochasticity in the initial number of DSBs and the DNA repair process, p53 and Mdm2 exhibit a coordinated oscillatory dynamics upon IR stimulation in single cells, with a stochastic number of oscillations whose mean increases with IR dose. The damped oscillations previously observed in cell populations can be explained as the aggregate behavior of single cell

2020-05-13 | MODEL2005130001 | BioModels

Tardigrades dramatically upregulate DNA repair pathway genes in response to ionizing radiation

Project description:Tardigrades can survive remarkable doses of ionizing radiation, up to about 1000 times the lethal dose for humans. How they do so is incompletely understood. We found that the tardigrade Hypsibius exemplaris suffers DNA damage upon gamma irradiation, but damage is repaired. We show that tardigrades have a specific and robust response to ionizing radiation: irradiation induces a rapid, dramatic upregulation of many DNA repair genes. By expressing tardigrade genes in bacteria, we validate that increased expression of some repair genes can suffice to increase radiation tolerance. We show that at least one such gene is necessary for tardigrade radiation tolerance. Tardigrades’ ability to sense ionizing radiation and massively upregulate specific DNA repair pathway genes may represent an evolved solution for maintaining DNA integrity.

2024-12-13 | PXD047724 | Pride

Expression data from H1299 and H460 lung cancer cell lines

Project description:To identify a set of genes related to radioresistance, we analyzed the time-series gene expression profiles of radioresistant H1299 and radiosensitive H460 lung cancer cells in response to 2 Gy of ionizing radiation (IR) by performing quadratic regression (QR) analysis. Out of the 21,331 genes, we selected 6,538 genes by QR analysis from the gene expression profile of H460 cells and 6,086 genes from that of H1299 cells. Most of the genes identified in the H460 cells were classified into continuously up- or down-regulated groups, while the major QR groups were transiently changed groups in the H1299 cell line. From gene ontology analysis of the major QR groups, the DNA damage response was commonly enriched in both cell lines. DNA repair-related genes such as ATM, ATR, TP53BP1, BRCA1, MRE11, NBN and RAD50 were particularly up-regulated in H1299 cells. Suppression of these DNA repair-related genes using siRNA made H1299 cells radiosensitive to ionizing radiation. The data suggest that differential responses to DNA damage confer radioresistance to cancer cells, and provide potential novel targets for sensitizing radiotherapy.

2010-02-27 | GSE20549 | GEO

Radiation-induced epigenetic DNA methylation modification of radiation-response pathways

2013-07-01 | GSE45958 | GEO

The tardigrade Hypsibius exemplaris dramatically upregulates DNA repair pathway genes in response to ionizing radiation [Bleo_RNA-seq]

Project description:Tardigrades can survive remarkable doses of ionizing radiation, up to about 1000 times the lethal dose for humans. How they do so is incompletely understood. We found that the tardigrade Hypsibius exemplaris suffers DNA damage upon gamma irradiation, but damage is repaired. We show that tardigrades have a specific and robust response to ionizing radiation: irradiation induces a rapid and dramatic upregulation of many DNA repair genes. By expressing tardigrade genes in bacteria, we validate that increased expression of some repair genes can suffice to increase radiation tolerance. We show that at least one such gene is necessary for tardigrade radiation tolerance. Tardigrades’ ability to sense ionizing radiation and massively upregulate specific DNA repair pathway genes may represent an evolved solution for maintaining DNA integrity.

2024-04-12 | GSE253470 | GEO

DNA damage and eIF4G1 in breast cancer cells reprogram translation for survival and DNA repair mRNAs

Project description:The cellular response to DNA damage is mediated through multiple pathways that regulate and coordinate DNA repair, cell cycle arrest and cell death. We show that the DNA damage response (DDR) induced by ionizing radiation (IR) is coordinated in breast cancer cells by selective mRNA translation mediated by high levels of translation initiation factor eIF4G1. Increased expression of eIF4G1, common in breast cancers, was found to selectively increase translation of mRNAs involved in cell survival and the DDR, preventing autophagy and apoptosis (Survivin, HIF1α, XIAP), promoting cell cycle arrest (GADD45a, p53, ATRIP, Chk1) and DNA repair (53BP1, BRCA1/2, PARP, Rfc2-5, ATM, MRE-11, others). Reduced expression of eIF4G1, but not its homolog eIF4G2, greatly sensitizes cells to DNA damage by IR, induces cell death by both apoptosis and autophagy, and significantly delays resolution of DNA damage foci with little reduction of overall protein synthesis. While some mRNAs selectively translated by higher levels of eIF4G1 were found to use internal ribosome entry site (IRES)-mediated alternate translation, most do not. The latter group shows significantly reduced dependence on eIF4E for translation, facilitated by an enhanced requirement for eIF4G1. Increased expression of eIF4G1 therefore promotes specialized translation of survival, growth arrest and DDR mRNAs that are important in cell survival and DNA repair following genotoxic DNA damage. The purpose of this study was to identify mRNAs that are selectively increased in translation by high levels of the initiation factor eIF4G1, which occurs in many advanced human cancers, in response to DNA damage caused by ionizing radiation,

2012-10-17 | GSE41627 | GEO

The tardigrade Hypsibius exemplaris dramatically upregulates DNA repair pathway genes in response to ionizing radiation [IR_RNA-seq]

Project description:Tardigrades can survive remarkable doses of ionizing radiation, up to about 1000 times the lethal dose for humans. How they do so is incompletely understood. We found that the tardigrade Hypsibius exemplaris suffers DNA damage upon gamma irradiation, but damage is repaired. We show that this tardigrade has a specific and robust response to ionizing radiation: irradiation induces a rapid upregulation of many DNA repair genes. This upregulation is unexpectedly extreme, making some DNA repair transcripts among the most abundant transcripts in the animal. By expressing tardigrade genes in bacteria, we validate that increased expression of some repair genes can suffice to increase radiation tolerance. We show that at least one such gene is important for tardigrade radiation tolerance. We hypothesize that tardigrades’ ability to sense ionizing radiation and massively upregulate specific DNA repair pathway genes may represent an evolved solution for maintaining DNA integrity.

2024-04-12 | GSE240501 | GEO

Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents

Project description:DNA repair competency is one determinant of sensitivity to certain chemotherapy drugs, such as cisplatin. Cancer cells with intact DNA repair can avoid the accumulation of genome damage during growth and also can repair platinum-induced DNA damage. We sought genomic signatures indicative of defective DNA repair in cell lines and tumors and correlated these signatures to platinum sensitivity. The number of subchromosomal regions with allelic imbalance extending to the telomere (NtAI) predicted cisplatin sensitivity in vitro and pathologic response to preoperative cisplatin treatment in patients with triple-negative breast cancer (TNBC). In serous ovarian cancer treated with platinum-based chemotherapy, higher levels of NtAI forecast a better initial response. We found an inverse relationship between BRCA1 expression and NtAI in sporadic TNBC and serous ovarian cancers without BRCA1 or BRCA2 mutation. Thus, accumulation of telomeric allelic imbalance is a marker of platinum sensitivity and suggests impaired DNA repair.

2012-03-22 | GSE28330 | GEO

Inherited C-terminal TREX1 variants disrupt homology-directed repair to cause senescence and DNA damage phenotypes in Drosophila, mice, and humans

Project description:Age-related microangiopathy, also known as small vessel disease (SVD), causes damage to the liver, brain, kidney and retina. Based on the DNA damage theory of aging, we reasoned that genomic instability may underlie an SVD caused by dominant C-terminal variants in TREX1, the most abundant 3’-5’ DNA exonuclease in mammals. C-terminal TREX1 variants cause an adult-onset SVD known as retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S). In RVCL, an aberrant, C-terminally truncated TREX1 mislocalizes to the nucleus due to deletion of its ER-anchoring domain. Since RVCL pathology mimics that of the radiation injury, we reasoned that nuclear TREX1 promotes DNA damage. Here, we show that RVCL-associated TREX1 variants cause DNA damage in humans, mice, and Drosophila, and that cells expressing RVCL mutant TREX1 are more vulnerable to DNA damage induced by chemotherapy and cytokines that up-regulate TREX1, leading to depletion of TREX1-high cells in RVCL mice. RVCL-associated TREX1 mutants inhibit homology-directed repair (HDR), causing DNA deletions and vulnerablility to PARP inhibitors. In women with RVCL, we observe early-onset breast cancer, similar to patients with BRCA1/2 variants. Our results provide a new mechanistic basis linking aberrant TREX1 activity to the DNA damage theory of aging, premature senescence, and microvascular disease.

2024-05-30 | PXD051905 | Pride

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