Ubiquitin ligase TRAIP plays an essential role during the S-phase of unperturbed cell cycle in the resolution of DNA replication – transcription conflicts
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ABSTRACT:
PROVIDER: PRJNA828557 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18839612.fastq.gz | Fastqsanger.gz | |||
| SRR18839613.fastq.gz | Fastqsanger.gz | |||
| SRR18839614.fastq.gz | Fastqsanger.gz | |||
| SRR18839615.fastq.gz | Fastqsanger.gz | |||
| SRR18839616.fastq.gz | Fastqsanger.gz |
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Project description:Cell division is the basis for the propagation of life and requires accurate duplication of all genetic information. DNA damage created during replication (replication stress) is a major cause of cancer, premature aging and a spectrum of other human disorders. TRAIP E3 ubiquitin ligase has been shown over the years to play a role in a number of the cellular processes that govern genome integrity and faultless segregation. TRAIP is essential for cell viability and mutations in TRAIP ubiquitin ligase activity lead to primordial dwarfism in patients. Here, for the first time we have determined the mechanism of inhibition of cell proliferation in TRAIP-depleted cells. We have taken advantage of the auxin induced degron system to rapidly degrade TRAIP within cells to dissect the importance of various functions of TRAIP in different stages of the cell cycle. We found that upon rapid TRAIP degradation cells cease to proliferate, arrest in G2 stage of the cell cycle and undergo senescence. TRAIP degradation in specific stages of the cell cycle revealed that TRAIP plays its essential role in S-phase and that the lack of TRAIP results in the generation of DNA damage at transcription start sites due to replication-transcription collisions.
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Project description:We identified the ubiquitin ligase Huwe1 as a crucial regulator of hematopoietic stem cell (HSC) functions. We generated Huwe1 conditional knock-out mice and discovered that the loss of this ligase causes an increased proliferation and stem cell exhaustion, together with a decreased lymphoid specification in vivo. We observed that the ubiquitin ligase Huwe1 is controlling the expression of N-myc at the level of the most immature stem and progenitor hematopoietic populations, mediating the described effects. Hematopoietic stem cells (HSC) from the bone marrow of transgenic animals carrying a N-myc/mCherry fusion gene were sorted according to N-myc expression (defined by mCherry) into N-myc high and low subpopulations. Each of these 2 populations was subjected to microarray gene expression profiling.
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Project description:In the 1950s the drug thalidomide administered as a sedative to pregnant women led ot the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and ist IMiD derivatives recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4(CRBN)) ubiquitin ligase. Through an unbiased screen we identify the homeobox trranscription factor MEIS2 as an endogenous substrate of CRL4(CRBN).
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Project description:The TRIM37 gene is mutatedin Mulbery nanism, a rare autosomal recessive disorder, and is in the 17q23 chromosomal region that is amplified in up to ~40% of breast cancers. Trim37 contains a RING finger domain, a hallmark of E3 ubiquitin ligases, but the protein substrate(s) of Trim37 is unknown. Mono-ubiquitination of histone H2A is a chromatin modification associated with transcriptional repression and here we report that Trim37 is an H2A ubiquitin ligase. Genome-wide Chip-CHIP experiments indicate that in human breast cancer cells containing amplified 17q23, Trim37 is bound to the promoters of many tumor suppressor genes. RNA interference (RNAi)-mediated knockdown of Trim37 results in loss of ubiquitinated H2A, dissociation of PRC1 and PRC2, and transcriptional reactivation of silenced genes. Knockdown of Trim37 in human breast cancer cells containing amplified 17q23 substantially decreases tumor growth in mouse xenografts. Collectively, our results reveal Trim37 as a new H2A ubiquitin ligase that is overexpressed in a subset of breast cancers and redirects PRC2 to silence tumor suppressors and other genes resulting in oncogenesis. Identification of TRIM37 Binding targets in MCF7 cells from the two replicate experiments
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Project description:We identified the ubiquitin ligase Huwe1 as a crucial regulator of hematopoietic stem cell (HSC) functions. We generated Huwe1 conditional knock-out mice and discovered that the loss of this ligase causes an increased proliferation and stem cell exhaustion, together with a decreased lymphoid specification in vivo. We observed that the ubiquitin ligase Huwe1 is controlling the expression of N-myc at the level of the most immature stem and progenitor hematopoietic populations, mediating the described effects.
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Project description:The E3 ubiquitin ligase UHRF1 is an established cofactor for replication-coupled DNA methylation inheritance. The current model posits a stepwise pathway in which UHRF1 engages nucleosomes through histone and DNA binding. This multivalent nucleosome readout directs UHRF1 ubiquitin ligase activity toward several lysines on N-terminal tails of histone H3, binding sites for DNMT1 through tandem ubiquitin interacting motifs (UIM1 and UIM2). While this elegant chromatin regulatory mechanism is now taking shape, the extent to which ubiquitin signaling through UHRF1 contributes to DNMT1-dependent DNA methylation maintenance genome-wide is not known. Here, we present comparative, genome-scale analysis of DNA methylation inheritance in human colon cancer cells with compromised UHRF1 ubiquitin ligase and DNMT1 ubiquitin reading activities. We reveal that DNA methylation maintenance in contexts of low CpG density is particularly vulnerable to disruption of UHRF1 ubiquitin ligase activity. This low CpG density hypomethylation signature, a common feature of partially methylated domains (PMDs) in human cancers, is also seen when DNMT1 ubiquitin reading activity through UIM1 is disrupted. Notably, disrupting UIM2 function affects DNA methylation inheritance to a similar extent as a catalytically dead form of the enzyme. Collectively, these studies demonstrate that DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process and suggest that a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to the development of PMDs in human cancers.
2024-10-23 | GSE256028 | GEO
Project description:The E3 ubiquitin ligase UHRF1 is an established cofactor for replication-coupled DNA methylation inheritance. The current model posits a stepwise pathway in which UHRF1 engages nucleosomes through histone and DNA binding. This multivalent nucleosome readout directs UHRF1 ubiquitin ligase activity toward several lysines on N-terminal tails of histone H3, binding sites for DNMT1 through tandem ubiquitin interacting motifs (UIM1 and UIM2). While this elegant chromatin regulatory mechanism is now taking shape, the extent to which ubiquitin signaling through UHRF1 contributes to DNMT1-dependent DNA methylation maintenance genome-wide is not known. Here, we present comparative, genome-scale analysis of DNA methylation inheritance in human colon cancer cells with compromised UHRF1 ubiquitin ligase and DNMT1 ubiquitin reading activities. We reveal that DNA methylation maintenance in contexts of low CpG density is particularly vulnerable to disruption of UHRF1 ubiquitin ligase activity. This low CpG density hypomethylation signature, a common feature of partially methylated domains (PMDs) in human cancers, is also seen when DNMT1 ubiquitin reading activity through UIM1 is disrupted. Notably, disrupting UIM2 function affects DNA methylation inheritance to a similar extent as a catalytically dead form of the enzyme. Collectively, these studies demonstrate that DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process and suggest that a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to the development of PMDs in human cancers.
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Project description:The E3 ubiquitin ligase UHRF1 is an established cofactor for replication-coupled DNA methylation inheritance. The current model posits a stepwise pathway in which UHRF1 engages nucleosomes through histone and DNA binding. This multivalent nucleosome readout directs UHRF1 ubiquitin ligase activity toward several lysines on N-terminal tails of histone H3, binding sites for DNMT1 through tandem ubiquitin interacting motifs (UIM1 and UIM2). While this elegant chromatin regulatory mechanism is now taking shape, the extent to which ubiquitin signaling through UHRF1 contributes to DNMT1-dependent DNA methylation maintenance genome-wide is not known. Here, we present comparative, genome-scale analysis of DNA methylation inheritance in human colon cancer cells with compromised UHRF1 ubiquitin ligase and DNMT1 ubiquitin reading activities. We reveal that DNA methylation maintenance in contexts of low CpG density is particularly vulnerable to disruption of UHRF1 ubiquitin ligase activity. This low CpG density hypomethylation signature, a common feature of partially methylated domains (PMDs) in human cancers, is also seen when DNMT1 ubiquitin reading activity through UIM1 is disrupted. Notably, disrupting UIM2 function affects DNA methylation inheritance to a similar extent as a catalytically dead form of the enzyme. Collectively, these studies demonstrate that DNMT1-dependent DNA methylation inheritance is a ubiquitin-regulated process and suggest that a disrupted UHRF1-DNMT1 ubiquitin signaling axis contributes to the development of PMDs in human cancers.
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Project description:In the 1950s the drug thalidomide administered as a sedative to pregnant women led ot the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and ist IMiD derivatives recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4(CRBN)) ubiquitin ligase. Through an unbiased screen we identify the homeobox trranscription factor MEIS2 as an endogenous substrate of CRL4(CRBN). By definition, a specific target of CRL4(CRBN) is expected to have a very low intensity on negative control arrays (E1_E2), (E1_CRBN), (E1_E2_Cdt2), (E1_E2_Cdt2_revlimid), (E1_E2_Cdt2_CSN) or with CRL4(CRBN) in presence of inhibitor (E1_E2_CRBN_revlimid) and high intensity on arrays with CRL4(CRBN) (E1_E2_CRBN) or CRL4(CRBN) in presence of CSN (E1_E2_CRBN_CSN) Accordingly 16 protein microarrays were subjected to in vitro ubiquitylation using the following enzyme combinations: 3x Uba1+UbcH5a; 2x Uba1+UbcH5a+CRL4(DDB2); 3x Uba1+UbcH5a+CRL4(CRBN); 2x Uba1+UbcH5a+CRL4(CRBN)+lenalidomide; 2x Uba1+UbcH5a+CRL4(CRBN)+CSN; 2x Uba1+UbcH5a+CRL4(Cdt2); 1x Uba1+UbcH5a+CRL4(Cdt2)+CSN; 1x Uba1+UbcH5a+CRL4(Cdt2)+lenalidomide
2014-05-13 | E-GEOD-57554 | biostudies-arrayexpress