Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Expression data from control and Mbd4 KO CH12 cells that were activated with CIT for 24 hours.

ABSTRACT: AID-dependent U/G mismatches in S DNA are converted by BER and MMR DNA pathways into double-stranded breaks that are required for optimal CSR in activated B cells. Deficits in MMR proteins, MSH2, MLH1, and PMS2 result in lower CSR frequencies that are coupled with impaired DSB formation. MBD4 interacts with MLH1 and has been postulated to coordinate mismatch repair of U/G. Deletions of Mbd4 targeting the 5' end of the gene in mice do not affect CSR . However, Mbd4 transcription is complex, with the propensity to create alternative transcripts, including residual transcription leading to to truncated protein expression that complicates ananlysis in these mice. We describe a novel function of MBD4 housed in the C-terminus that is critical for DSB formation, which shares several characteristics with MMR . We conclude that the 3' end of the Mbd4 gene positively contributes to CSR and likely intersects the MMR pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE51559 | GEO | 2013/12/19

SECONDARY ACCESSION(S): PRJNA223410

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Expression data from control and Mbd4 KO CH12 cells that were activated with CIT for 24 hours.

Project description:AID-dependent U/G mismatches in S DNA are converted by BER and MMR DNA pathways into double-stranded breaks that are required for optimal CSR in activated B cells. Deficits in MMR proteins, MSH2, MLH1, and PMS2 result in lower CSR frequencies that are coupled with impaired DSB formation. MBD4 interacts with MLH1 and has been postulated to coordinate mismatch repair of U/G. Deletions of Mbd4 targeting the 5' end of the gene in mice do not affect CSR . However, Mbd4 transcription is complex, with the propensity to create alternative transcripts, including residual transcription leading to to truncated protein expression that complicates ananlysis in these mice. We describe a novel function of MBD4 housed in the C-terminus that is critical for DSB formation, which shares several characteristics with MMR . We conclude that the 3' end of the Mbd4 gene positively contributes to CSR and likely intersects the MMR pathway. 2 independent samples for each control and Mbd4 KO group

2013-12-19 | E-GEOD-51559 | biostudies-arrayexpress

MBD4 loss results in global reactivation of promoters and retroelements with low methylated CpG density.

Project description:Inherited defects in the base-excision repair gene MBD4 predispose individuals to adenomatous polyposis and colorectal cancer, which is characterized by an accumulation of C>T transitions resulting from spontaneous deamination of 5’-methylcytosine. Despite its significance, this DNA repair pathway is still poorly understood. Here we show that the protein MBD4 is required for DNA methylation maintenance and G/T mismatch repair. Transcriptome and methylome analyses reveal a genome-wide hypomethylation of promoters, gene bodies and repetitive elements in the absence of MBD4 in vivo. Methylation mark loss is accompanied by a broad transcriptional derepression phenotype affecting promoters and retroelements with low methylated CpG density. MBD4 in vivo forms a complex with the mismatch repair proteins (MMR), which exhibits high bi-functional glycosylase/AP-lyase endonuclease specific activity towards methylated DNA substrates containing a G/T mismatch. Experiments using recombinant proteins reveal that the association of MBD4 with the MMR protein MLH1 is required for this activity. The described data identify MBD4 as an enzyme specifically designed to repair deaminated 5-methylcytosines and illustrates how MBD4 functions in normal and pathological conditions.

2022-01-10 | GSE84497 | GEO

MBD4 loss results in global reactivation of promoters and retroelements with low methylated CpG density.

2022-01-10 | GSE84319 | GEO

MBD4 loss results in global reactivation of promoters and retroelements with low methylated CpG density.

2022-01-10 | GSE84318 | GEO

DNA mismatch repair activity of MutLα is regulated by CK2-dependent phosphorylation of MLH1 (S477)

Project description:MutLα, a heterodimer consisting of MLH1 and PMS2, is a key player of DNA mismatch repair (MMR), yet little is known about its regulation. In this study, we used mass spectrometry to identify phosphorylated residues within MLH1 and PMS2. The most frequently detected phosphorylated amino acid was serine 477 of MLH1. Isolation of nuclear and cytoplasmic fractions showed that p-MLH1S477 remains predominantly in the cytoplasm. Pharmacological treatment indicates that Casein Kinase II (CK2) could be responsible for the phosphorylation of MLH1 at serine 477 in vivo. In vitro kinase assay verified MLH1 as a substrate of CK2. Most importantly, using in vitro MMR assay we could demonstrate that p-MLH1S477 lost MMR activity while the activity of MLH1S477A, which could not be phosphorylated at position S477, was not modified. In summary, we identified that post-translational phosphorylation of MLH1 by CK2 at amino acid position 477 can switch off MMR activity in vitro. Since CK2 is overexpressed in many tumors and is able to inactivate MMR by phosphorylation of MLH1, the new mechanism here described could have an important impact on tumors overactive in CK2.

2018-08-28 | PXD009524 | Pride

DNA mismatch repair activity of MutLalpha is regulated by CK2-dependent phosphorylation of MLH1

Project description:Mass spectrometry based PTM phosphorylation analysis to study regulation mechanism of MUTL alpha, a heterodimer consisting of MLH1 and PMS2 and a key player in DNA mismatch repair (MMR). It could be demonstrated that phosphorylation of MLH1 by Casein Kinase II (CK2) at amino acid position 477 can switch off MMR activity in vitro.

2018-08-29 | PXD009026 | Pride

Disentangling the mutational effects on protein stability and interaction of human MLH1

Project description:Missense mutations can have diverse effects on proteins, depending on their location within the protein and the specific amino acid substitution. Mutations in the DNA mismatch repair gene MLH1 are associated with Lynch syndrome, yet the underlying mechanism of most disease-causing mutations remain elusive. To address this gap, we aim to disentangle the mutational effects on two essential properties for MLH1 function: protein stability and protein-protein interaction. We systematically examine the cellular abundance and interaction with PMS2 of 4839 (94%) MLH1 variants in the C-terminal domain. Our combined data shows that most MLH1 variants lose interaction with PMS2 due to reduced cellular abundance. However, substitutions to charged residues in the canonical interface lead to reduced interaction with PMS2. Unexpectedly, we also identify a distal region in the C-terminal domain of MLH1 where substitutions cause both decreased and increased binding with PMS2. Our data successfully distinguish benign from pathogenic MLH1 variants and correlate with thermodynamic stability predictions and evolutionary conservation. This work provides mechanistic insights into variant consequences and may help interpret MLH1 variants.

2024-08-01 | GSE273652 | GEO

Expression data from primary gastric tumors (MSI and MSS) and adjacent normal samples

Project description:Gastric cancers with mismatch repair (MMR) inactivation are characterised by microsatellite instability (MSI). In this study, the transcriptional profile of 38 gastric cancers with and without MSI was analysed. Unsupervised analysis showed that the immune and apoptotic gene networks efficiently discriminated these two cancer types. Hierarchical clustering analysis revealed numerous gene expression changes associated with the MSI phenotype. Amongst these, the p53-responsive genes maspin and 14-3-3 sigma were significantly more expressed in tumours with than without MSI. A tight immunosurveillance coupled with a functional p53 gene response is consistent with the better prognosis of MSI cancers. Frequent silencing of MLH1 and downregulation of MMR target genes, such as MRE11 and MBD4, characterised MSI tumours. The downregulation of SMUG1 was also a typical feature of these tumours. The DNA repair gene expression profile of gastric cancer with MSI is of relevance for therapy response.

2008-12-18 | GSE13911 | GEO

The RON receptor tyrosine kinase promotes metastasis by triggering epigenetic reprogramming through the thymine glycosylase MBD4 (Bisulfite-Seq)

Project description:Metastasis is the major cause of death in cancer patients, yet the genetic/epigenetic programs that drive metastasis are poorly understood. Here, we report a novel epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by activation of the RON receptor tyrosine kinase by its ligand, macrophage stimulating protein (MSP). Through PI3K signaling, RON/MSP promotes expression of the G:T mismatch-specific thymine glycosylase MBD4. RON/MSP and MBD4-dependent aberrant DNA methylation results in misregulation of a specific set of genes. Knockdown of MBD4 reverses methylation at these specific loci, and blocks metastasis. We also show that the MBD4 glycosylase catalytic residue is required for RON/MSP-driven metastasis. Analysis of human breast cancers using a set of specific genes that are regulated by RON/MSP through MBD4-directed aberrant DNA methylation revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a new pharmacological agent prevents activation of the RON/MBD4 pathway and blocks metastasis of patient-derived breast tumor grafts in vivo.

2014-01-02 | GSE52688 | GEO

The RON receptor tyrosine kinase promotes metastasis by triggering epigenetic reprogramming through the thymine glycosylase MBD4 (RNA-Seq)

2014-01-02 | GSE52687 | GEO