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Role of NFBD1 in global gene expression

ABSTRACT: NFBD1 (nuclear factor with BRCT domains 1), also known as MDC1 (mediator of DNA damage signaling 1), is a protein involved in the ATM signaling pathway in response to DNA damage. In addition to a role in signaling, NFBD1 possesses transactivation activity, suggesting that it may influence transcription. Furthermore, NFBD1 affects p53-mediated transcription in the presence of the DNA damaging agent adriamycin. Our goal was to determine if NFBD1 affects global gene expression with or without ionizing radiation-induced DNA damage. Moreover, we sought to separate p53-dependent from p53-independent events. Illumina microarray analysis was carried out on RNA extracted from cells treated with and without NFBD1 shRNA and/or p53 shRNA in the presence and absence of DNA damage. Surprisingly, we found that the expression of NFBD1-regulated genes was changed in both the presence and absence of DNA damage. Furthermore, most NFBD1-regulated genes were regulated independently of p53. The identification of NFBD1-regulated genes was confirmed with a second NFBD1-directed shRNA sequence.

ORGANISM(S): Homo sapiens

PROVIDER: GSE23010 | GEO | 2011/06/16

SECONDARY ACCESSION(S): PRJNA129917

REPOSITORIES: GEO

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Role of NFBD1 in global gene expression

Project description:NFBD1 (nuclear factor with BRCT domains 1), also known as MDC1 (mediator of DNA damage signaling 1), is a protein involved in the ATM signaling pathway in response to DNA damage. In addition to a role in signaling, NFBD1 possesses transactivation activity, suggesting that it may influence transcription. Furthermore, NFBD1 affects p53-mediated transcription in the presence of the DNA damaging agent adriamycin. Our goal was to determine if NFBD1 affects global gene expression with or without ionizing radiation-induced DNA damage. Moreover, we sought to separate p53-dependent from p53-independent events. Illumina microarray analysis was carried out on RNA extracted from cells treated with and without NFBD1 shRNA and/or p53 shRNA in the presence and absence of DNA damage. Surprisingly, we found that the expression of NFBD1-regulated genes was changed in both the presence and absence of DNA damage. Furthermore, most NFBD1-regulated genes were regulated independently of p53. The identification of NFBD1-regulated genes was confirmed with a second NFBD1-directed shRNA sequence. The role of NFBD1 in global gene expression both in the presence and absence of ionizing radiation was determined. p53-dependent and p53-dependent events regulated by NFBD1 depletion were studied. U2OS cells were treated with control, NFBD1 shRNA, and/or p53 shRNA-expressing retrovirus. Cells were then treated with ionizing radiation and total RNA was isolated for Illumina microarray analysis.

2011-06-16 | E-GEOD-23010 | biostudies-arrayexpress

MDC1 interacts with TOPBP1 to maintain chromosomal stability during mitosis

Project description:MDC1 is a large, modular phospho-protein scaffold that mediates recruitment of signaling and repair complexes to sites of DNA double-strand breaks (DSBs). MDC1 is anchored to damaged chromatin through interaction of its C-terminal BRCT-repeat domain with phosphorylated H2AX (γH2AX), where it recruits downstream factors via direct phosphorylation-dependent protein-protein interactions. Here, using unbiased proteomic analyses we identify a highly conserved protein interaction surface near the MDC1 N-terminus for the DNA damage response protein TOPBP1. We show that TOPBP1 directly binds to two residues in MDC1 that are phosphorylated by CK2. Interestingly, we find that TOPBP1 recruitment to DSBs depends on direct interaction with MDC1 only during mitosis. Furthermore, we demonstrate that disrupting MDC1-TOPBP1 binding causes hypersensitivity to ionizing radiation in mitosis, as well as increased micronuclei and chromosomal instability. Thus, our results highlight an important and hitherto unnoticed function for MDC1 and TOPBP1 in maintaining genome stability during cell division.

2019-03-25 | PXD011850 | Pride

Iwamoto2010 - Cell cycle reponse to DNA damage

Project description:After DNA damage, cells activate p53, a tumor suppressor gene, and select a cell fate (e.g., DNA repair, cell cycle arrest, or apoptosis). Recently, a p53 oscillatory behavior was observed following DNA damage. However, the relationship between this p53 oscillation and cell-fate selection is unclear. Here, we present a novel model of the DNA damage signaling pathway that includes p53 and whole cell cycle regulation and explore the relationship between p53 oscillation and cell fate selection. The simulation run without DNA damage qualitatively realized experimentally observed data from several cell cycle regulators, indicating that our model was biologically appropriate. Moreover, the comprehensive sensitivity analysis for the proposed model was implemented by changing the values of all kinetic parameters, which revealed that the cell cycle regulation system based on the proposed model has robustness on a fluctuation of reaction rate in each process. Simulations run with four different intensities of DNA damage, i.e. Low-damage, Medium-damage, High-damage, and Excess-damage, realized cell cycle arrest in all cases. Low-damage, Medium-damage, High-damage, and Excess-damage corresponded to the DNA damage caused by 100, 200, 400, and 800 J/m(2) doses of UV-irradiation, respectively, based on expression of p21, which plays a crucial role in cell cycle arrest. In simulations run with High-damage and Excess-damage, the length of the cell cycle arrest was shortened despite the severe DNA damage, and p53 began to oscillate. Cells initiated apoptosis and were killed at 400 and 800 J/m(2) doses of UV-irradiation, corresponding to High-damage and Excess-damage, respectively. Therefore, our model indicated that the oscillatory mode of p53 profoundly affects cell fate selection.

2020-04-27 | BIOMD0000000939 | BioModels

Pereira2020 - NRF2–p53 integrated-systems model of oxidative stress

Project description:Integrated-systems model of oxidative stress connecting NRF2 and p53 signaling pathways. Additional crosstalk linking oxidative stress to p53 inhibition, p53 to NRF2 through p21, and NRF2 to MDM2 was incorporated in this model. The NRF2 pathway was encoded as first- and second-order rate equations for KEAP1 oxidation and NRF2 stabilization; NRF2-mediated transcription of antioxidant enzymes was modeled as a Hill function. The p53 pathway was reconstructed from a delay differential equation model of p53 signaling in response to DNA damage. To adapt the p53 DNA-damage model to respond to oxidative stress, we used a first-order oxidation reaction of ATM/CHEK2 by intracellular H2O2. The integrated base model of NRF2–p53 oxidative-stress signaling contains 42 reactions and 22 ordinary differential equations (ODEs).

2021-10-29 | MODEL2110270001 | BioModels

Comparison of gene expression between wild-type and PTIP deficient chicken DT40 B cells

2009-10-28 | GSE18778 | GEO

Comparison of gene expression between wild-type and PTIP deficient chicken DT40 B cells

Project description:PTIP (Pax2 transactivation domain-interacting protein) is a nuclear protein containing six BRCT domains. It has been shown that PTIP affects gene expression by controlling the activity of the transcription factor Pax2 and histone H3 lysine 4 methyltransferase complexes. In addition to its role in transcriptional regulation, PTIP has been implicated in DNA damage response. To ask if the depletion of PTIP affects the expression level of genes encoding DNA damage response factors , we compared the whole transcripts between wild-type and PTIP deficient chicken DT40 B cell lines. The total RNAs were isolated from wild-type and PTIP deficient cells (PTIP-/-/-) using Sepasol®-RNA I (Nacalai tesque, Japan). The gene expression profiles were examined using Genechip® Chicken Genome Array (Affymetrix Cat #900590), by GeneticLab co. Ltd. Japan, following Genechip® protocol.

2009-10-27 | E-GEOD-18778 | biostudies-arrayexpress

MDC1 maintains active elongation complexes of RNA polymerase II

Project description:The role of MDC1 in the DNA damage response has been extensively studied, however, its impact on other cellular processes is not well understood. Here, we describe a role for MDC1 in transcription by regulating the activity of the RNAPolymerase II (RNAPII). Depletion of MDC1 caused a genome-wide reduction in the abundance of actively engaged RNAPII elongation complexes throughout the gene body of protein coding genes under unperturbed conditions. Decreased engaged RNAPII subsequently alters the assembly of the spliceosome complex on chromatin, leading to defects in pre-mRNA splicing. Mechanistically, the S/TQ domain of MDC1 modulates RNAPII-mediated transcription. Upon genotoxic stress, MDC1 promotes the abundance of engaged RNAPII complexes at DNA breaks, thereby stimulating nascent transcription at the damaged sites. Of clinical relevance, cancer cells lacking MDC1 display hypersensitivity to RNAPII inhibitors. Overall, we unveil a previously uncharacterized role of MDC1 in RNAPII-mediated transcription with potential implications for cancer treatment.

2022-11-24 | GSE215990 | GEO

Exogenous BRCT-GST of PARP1 bind to wild-type p53. p53 was overexpressed after UV treatment in U2OS.

Project description:Exogenous BRCT-GST in U2OS bind to wild-type p53 in a phosphorylation-dependent manner, after UV treatment. BRCT-GST fusion protected cells from apoptotic cell death and impact of miRNAs responsive to p53 activation.

2024-03-02 | E-MTAB-3628 | biostudies-arrayexpress

CTDP1 BRCT domain PPI - CTDP1 regulates breast cancer survival and DNA repair through BRCT-specific interactions with FANCI

Project description:The BRCT domain is commonly found in DNA damage response proteins, but its role in the phosphatase CTDP1 is unknown. This project examined the protein-protein interactions (PPI) associated with the CTDP1 BRCT domain region only and identified 106 significant interacting partners. Many of these partners play prominent roles in distinct DNA damage repair pathways and reveal novel functions of CTDP1 in these pathways.

2019-06-04 | PXD009541 | Pride

Extracts from sweet sorghum (Sorghum bicolor), a feedstock for biorefining, suppressed proliferation and elevated apoptosis in human colon cancer stem cells via suppression of Wnt/beta-catenin signaling pathway

Project description:In colorectal cancer, p53 is commonly inactivated, associated with chemo-resistance, and marks the transition from non-invasive to invasive disease. Cancers, including colorectal cancer, are thought to be diseases of aberrant stem cell populations, as stem cells are able to self-renew, making them long-lived enough to acquire mutations necessary to manifest the disease. We have shown that extracts from sweet sorghum stalk components eliminate colon cancer stem cells (CCSC) in a partial p53-dependent fashion. However, the underlying mechanisms are unknown. In the present study, CCSC were transfected with short hairpin-RNA against p53 (CCSC p53 shRNA) and treated with sweet sorghum phenolics extracted from different plant components (dermal layer, leaf, seed head and whole plant). While all components demonstrated anti-proliferative and pro-apoptotic effects in CCSC, phenolics extracted from the dermal layer and seed head were more potent in eliminating CCSC by elevating caspases 3/7 activity, PARP cleavage, and DNA fragmentation in a p53-dependent and p53-independent fashion, respectively. Further investigations revealed that the anti-proliferative and pro-apoptotic effects were associated with decreases in beta-catenin protein levels, and beta-catenin targets cyclin D1, cMyc, and survivin. These results suggest that the anti-proliferative and pro-apoptotic effects of sweet sorghum extracts against human colon cancer stem cells are via suppression of Wnt/beta-catenin pro-survival signaling in a p53-dependent (dermal layer) and partial p53-independent (seed head) fashion. LCMS used to identify phenolic compounds associated with extract activity

2014-05-01 | MTBLS69 | MetaboLights

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