Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CRL4-DCAF15 control of cohesin dynamics sustains 1 cell proliferation

ABSTRACT: The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency. Loss of DCAF15 results in suppression of AML through compromised replication fork integrity and consequent accumulation of DNA damage. Accordingly, DCAF15 loss sensitizes AML to replication stress-inducing therapeutics. Mechanistically, we discover that DCAF15 directly interacts with the SMC1A protein of the cohesin complex and destabilizes the cohesin regulatory factors PDS5A and CDCA5. Loss of PDS5A and CDCA5 removal precludes cohesin acetylation on chromatin, resulting in uncontrolled chromatin loop extrusion, defective DNA replication, and apoptosis. Collectively, our findings uncover an endogenous, cell autonomous function of DCAF15 in sustaining AML proliferation through post-translational control of cohesin dynamics.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Luca Busino

PROVIDER: MSV000092697 | MassIVE | Sat Aug 19 08:58:00 BST 2023

SECONDARY ACCESSION(S): PXD044661

REPOSITORIES: MassIVE

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

CRL4-DCAF15 control of cohesin dynamics sustains cell proliferation [HiC]

Project description:The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency. Loss of DCAF15 results in suppression of AML through compromised replication fork integrity and consequent accumulation of DNA damage. Accordingly, DCAF15 loss sensitizes AML to replication stress-inducing therapeutics. Mechanistically, we discover that DCAF15 directly interacts with the SMC1A protein of the cohesin complex and destabilizes the cohesin regulatory factors PDS5A and CDCA5. Loss of PDS5A and CDCA5 removal precludes cohesin acetylation on chromatin, resulting in uncontrolled chromatin loop extrusion, defective DNA replication, and apoptosis. Collectively, our findings uncover an endogenous, cell autonomous function of DCAF15 in sustaining AML proliferation through post-translational control of cohesin dynamics.

2024-05-22 | GSE241580 | GEO

CRL4-DCAF15 control of cohesin dynamics sustains cell proliferation [RNA-seq_CRISPR]

2024-05-22 | GSE241578 | GEO

CRL4-DCAF15 control of cohesin dynamics sustains cell proliferation [ChIP-seq]

2024-05-22 | GSE241579 | GEO

CRL4-DCAF15 control of cohesin dynamics sustains cell proliferation [RNA-seq_dTAG]

2024-05-22 | GSE266010 | GEO

STAG2 mutations in leukemia alter cohesin ring function, DNA damage repair, and splicing

Project description:Genome compartmentalization mediated by the cohesin complex plays an essential role in the maintenance of genome integrity and transcriptional regulation. Recurrent somatic mutations in multiple members of the cohesin complex are frequent genetic drivers in several types of cancer, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but the cellular consequences of cohesin mutations have not been determined and no therapies have been identified with selective efficacy in cohesin-mutant cancers. Using quantitative proteomics and genome-wide genetic screens in genetically engineered models of STAG2-mutant AML, we identify changes in cohesin complex composition and dependency on STAG1, DNA damage repair, master transcription factors, and RNA splicing machinery. Consistent with these findings, loss of STAG2 leads to DNA replication fork stalling and is associated with increased levels of dsDNA breaks and activation of DNA damage checkpoints, as well as aberrant splicing. Genetic or pharmacologic perturbation of DNA damage repair or splicing creates a synthetic vulnerability for cohesin-mutant cells in vitro and in vivo. Finally, STAG2 loss leads to a global reduction in cohesin binding to chromatin and expansion of super-enhancers, and mutant cohesin complexes spatially co-localize with super-enhancer enriched factors, DNA damage and splicing machinery. Our findings inform the biology of cohesins in cancer cells, and highlight novel therapeutic possibilities for cohesin-mutant malignancies.

| MSV000082970 | MassIVE

CST interacts with the cohesin complex and promotes chromosome cohesion

Project description:Sister chromatid cohesion (SCC), the pairing of sister chromatids following DNA replication until mitosis, is established by loading of the cohesin complex on newly replicated chromatids. Cohesin must then be maintained until mitosis to prevent segregation defects and aneuploidy. However, how SCC is established and maintained until mitosis remains incompletely understood and emerging evidence suggests that replication stress may lead to premature SCC loss. Here, we report that the single-stranded DNA-binding protein CTC1-STN1-TEN1 (CST) aids in SCC. CST primarily functions in telomere length regulation but also has known roles in replication restart and DNA repair. Following depletion of CST subunits, we observed an increase in the complete loss of SCC. Additionally, we determined that CST associates with the cohesin complex. Unexpectedly, we did not find evidence of altered cohesion or mitotic progression in the absence of CST; however, we did find that treatment with various replication inhibitors increased the association between CST and cohesin. Since replication stress was recently shown to induce SCC loss, we hypothesized that CST may be required to maintain or remodel SCC following DNA replication fork stalling. In agreement with this idea, SCC loss was greatly increased in CST-depleted cells following exogenous replication stress. Based on our findings, we propose that CST aids in the maintenance of SCC at stalled replication forks to prevent premature cohesion loss.

2021-07-28 | PXD026264 | Pride

Cohesin Mutations in AML

Project description:Cohesin shapes the nuclear chromatin architecture, including enhancer-promoter interactions, and its components, of which especially STAG2 and RAD21, are frequently mutated in myeloid malignancies. To elucidate mechanisms of leukemogenesis associated with cohesin mutations in humans, we comprehensively characterized genetic, epigenetic, transcriptional, and chromatin conformational changes in acute myeloid leukemia (AML). To corroborate our findings, we performed complementary siRNA-mediated depletion of STAG2, its paralogue STAG1 or RAD21 in cord blood-derived CD34+ primary human hematopoietic stem and progenitor cells (HSPCs). We show that STAG2 mutations consistently lead to the loss of STAG2 protein and are associated with a specific set of co-occurring mutations, while STAG1 was never mutated in AML. Loss of STAG2 was frequently compensated by STAG1. Still, specific loci displayed altered cohesin occupancy, gene expression and corresponding changes in local chromatin activation as measured by H3K27ac enrichment and chromatin accessibility. High-throughput chromosome conformation capture (in-situ Hi-C) revealed significantly altered chromatin looping in cohesin-mutated AMLs, including weakened enhancer-promoter contacts with reduced, cohesin-dependent promoter activity. In HSPCs, we detected transcriptomic and epigenetic effects overlapping STAG2-mutant AML-specific changes following STAG2 knockdown (KD), that were not invoked by the depletion of STAG1. We also found that STAG2 loss in cultured HSPCs impaired the differentiation capacity, especially erythroid colony formation which maintained HSPC-like gene expression. This work establishes STAG2 as a key regulator of cohesin-associated chromatin architecture, gene expression and differentiation in the human hematopoietic system and identifies candidate target genes that may be implicated in leukemogenesis.

| EGAS00001007405 | EGA

Functional crosstalk between the cohesin loader and chromatin remodelers

Project description:The cohesin complex has crucial roles in many structural and functional aspects of chromosomes including sister chromatid cohesion, genome organization, gene transcription and DNA repair. Cohesin recruitment onto chromosomes requires nucleosome free DNA and a specialized cohesin loader complex comprised of the Scc2 and Scc4 subunits. The cohesin loader, in addition to stimulating cohesin ATP hydrolysis and facilitating topological loading onto DNA, leads cohesin to chromatin receptors such as the RSC chromatin remodeling complex. Here, we explore the cohesin loader-RSC interaction and show that its Scc4 subunit contacts a conserved RSC ATPase motor module. The cohesin loader enhances RSC chromatin remodeling activity in vitro, as well as promoter nucleosome eviction in vivo. These findings provide insight into how the cohesin loader recognizes, as well as influences, the chromatin landscape, with implications for our understanding of human developmental disorders including Cornelia de Lange and Coffin-Siris syndromes.

2022-11-29 | PXD033446 | Pride

Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites

Project description:During cell division, transcription factors (TFs) are removed from chromatin twice, during DNA synthesis, and during condensation of chromosomes. How TFs can efficiently find their sites following these stages has been unclear. Here, we have analyzed the binding pattern of expressed TFs in human colorectal cancer cells. We find that binding of TFs is highly clustered, and that the clusters are enriched in binding motifs for several major TF classes. Strikingly, almost all clusters are formed around cohesin, and loss of cohesin decreases both DNA accessibility and binding of TFs to clusters. We show that cohesin remains bound in S phase, holding the nascent sister chromatids together at the TF cluster sites. Furthermore, cohesin remains bound to the cluster sites when TFs are evicted in early M-phase. These results suggest that cohesin binding functions as a cellular memory that promotes re- stablishment of TF clusters after DNA replication and chromatin condensation. Examination of TF binding by ChIP-seq in LoVo CRC cell-lines.

2013-08-15 | E-GEOD-49402 | biostudies-arrayexpress

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML

Project description:The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer including myelodysplatic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of STAG2-mutant AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to PARP inhibition. We developed a mouse model of MDS in which Stag2 mutations arise as clonal secondary lesions in the background of clonal hematopoiesis driven by Tet2 mutations, and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which is associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and RPA proteins. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.

2021-01-19 | GSE165038 | GEO

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