Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in human cancer
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ABSTRACT:
PROVIDER: PRJNA435577 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6761890_1.fastq.gz | Fastqsanger.gz | |||
| SRR6761890_2.fastq.gz | Fastqsanger.gz | |||
| SRR6761881_1.fastq.gz | Fastqsanger.gz | |||
| SRR6761881_2.fastq.gz | Fastqsanger.gz | |||
| SRR6761891_1.fastq.gz | Fastqsanger.gz |
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Project description:A synthetic lethality-based strategy has been developed to identify therapeutic targets in cancer harboring tumor-suppressor gene mutations, as exemplified by the effectiveness of poly ADP-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental or indispensable functions in the cell. Here, we developed an approach to identifying the "essential lethality" arising from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. We uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancer, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival, and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells led to premature chromatid separation, dramatic extension of mitotic duration, and consequently, lethal failure of cell division. More importantly, depletion of SA1 rendered those SA2-mutated cells more susceptible to DNA damage, especially double-strand breaks (DSBs), due to reduced functionality of DNA repair. Furthermore, inhibition of SA1 sensitized the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors.
| S-EPMC6025969 | biostudies-literature
Project description:Synthetic lethality-based strategy has been developed to identify therapeutic targets in cancer harboring tumor suppressor gene mutations, as exemplified by the effectiveness of poly(ADP)-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental housekeeping functions in the cell. Here we explore an approach to identify the “essential lethality” arose from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. In additional to the known synthetic-lethal interactions, this approach uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancers, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells leads to premature chromatid separation and dramatic extension of mitotic duration, which is accompanied by lethal failure of cell division. More importantly, depletion of SA1 renders those SA2-mutated cells not only more susceptible to DNA damage, especially double-strand breaks (DSBs), but also defective in DNA repair. Furthermore, inhibition of SA1 sensitizes the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors. This study provides a framework for the discovery of therapeutic targets in cancers that harbor specific essential gene deficiency.
2021-02-22 | GSE111004 | GEO
Project description:Rad21 is a subunit of cohesin. The main function of cohesin is to hold replicated chromosomes together until cells divide, but it also plays a role in gene expression. To find out which genes might be regulated by cohesin, a study was conducted to look for global changes in gene expression in zebrafish embryos lacking cohesin component Rad21. The zebrafish Rad21 mutant used for expression analysis was rad21nz171, an allele isolated in a forward genetic screen for regulators of runx1. Experiment Overall Design: RNA from rad21nz171 mutant and wild type zebrafish embryos collected at 24 hours post-fertilization (h.p.f.) and 48 h.p.f. was hybridized to Affymetrix microarrays (Gene Chip zebrafish genome arrays cat. no. 900488). Four pools of 50 embryos for each genotype and time point were used as the RNA source, and RNA from each pool was hybridized independently such that the experiment had four biological replicates.
2009-11-10 | E-GEOD-18795 | biostudies-arrayexpress
Project description:The cohesin complex links DNA molecules and plays key roles in the organization, expression, repair, and segregation of eukaryotic genomes. In vertebrates the Esco1 and Esco2 acetyltransferases both modify cohesin’s Smc3 subunit to establish sister chromatid cohesion during S phase, but differ in their N-terminal domains and expression during development and across the cell cycle. Here we show that Esco1 and Esco2 also differ dramatically in their interaction with chromatin, as Esco1 is recruited by cohesin to over 11,000 sites, whereas Esco2 is infrequently enriched at REST/NRSF target genes. Esco1’s colocalization with cohesin occurs throughout the cell cycle and depends on two short motifs (the A-box and B-box) present in and unique to all Esco1 orthologs. Deleting either motif led to the derepression of Esco1-proximal genes and functional uncoupling of cohesion from Smc3 acetylation. In contrast, other mutations that preserved Esco1’s recruitment separated its roles in cohesion establishment and gene silencing. We conclude that Esco1 uses cohesin as both a substrate and a scaffold for coordinating multiple chromatin-based transactions in somatic cells. Total RNA was isolated after treatment with indicated siRNAs, or transfection reagent only for control samples. Samples for each group in triplicate were processed for Illumina bead arrays (Illumina HT-12) by the MSKCC genomics core facility according to manufacturer instructions.
2015-08-25 | E-GEOD-71420 | biostudies-arrayexpress
Project description:Rad21 is a subunit of cohesin. The main function of cohesin is to hold replicated chromosomes together until cells divide, but it also plays a role in gene expression. To find out which genes might be regulated by cohesin, a study was conducted to look for global changes in gene expression in zebrafish embryos lacking cohesin component Rad21. The zebrafish Rad21 mutant used for expression analysis was rad21nz171, an allele isolated in a forward genetic screen for regulators of runx1.
2009-10-30 | GSE18795 | GEO
Project description:RAD21 is a subunit of cohesin. Cohesin is maninly known for its role in holding sister chromatids together during cell-division but it also plays a role in gene regulation. Genome wide study in MCF7 cells have shown that cohesin co-binds with estrogen receptor alpha at numerous sites. To identify estrogen sensitive genes that are influenced by cohesin, a microarray expression analysis was conducted in MCF7 cells lacking the cohesin subunit RAD21. Global changes in gene expression were identified in cells treated with Control/RAD21 siRNA and stimulated with estrogen/vehicle thereafter.
2016-01-30 | GSE59908 | GEO
Project description:The cohesin complex links DNA molecules and plays key roles in the organization, expression, repair, and segregation of eukaryotic genomes. In vertebrates the Esco1 and Esco2 acetyltransferases both modify cohesin’s Smc3 subunit to establish sister chromatid cohesion during S phase, but differ in their N-terminal domains and expression during development and across the cell cycle. Here we show that Esco1 and Esco2 also differ dramatically in their interaction with chromatin, as Esco1 is recruited by cohesin to over 11,000 sites, whereas Esco2 is infrequently enriched at REST/NRSF target genes. Esco1’s colocalization with cohesin occurs throughout the cell cycle and depends on two short motifs (the A-box and B-box) present in and unique to all Esco1 orthologs. Deleting either motif led to the derepression of Esco1-proximal genes and functional uncoupling of cohesion from Smc3 acetylation. In contrast, other mutations that preserved Esco1’s recruitment separated its roles in cohesion establishment and gene silencing. We conclude that Esco1 uses cohesin as both a substrate and a scaffold for coordinating multiple chromatin-based transactions in somatic cells.
2015-08-25 | GSE71420 | GEO
Project description:We used ChIP-seq to measure the binding of the cohesin subunit Rad21 in response to daunorubicin treatment in HCT116 cells
2016-09-30 | GSE86191 | GEO
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
Project description:Analysis of gene expression changes in mESCs where the cohesin subunit Scc1 has been depleted. There are 6 samples. 3 Scc1 wt/wt ERT2-Cre biological replicas and 3 Scc1 lox/lox ERT2-Cre biological replicas, all treated with 4'-OHT 80nM final concentration for 24h. Scc1 wt/wt and Scc1 lox/lox ERT2-Cre mES cells where grown in N2B27 +2i+LIF medium (Ying et al. 2008) for 24h in the presence of 80mM 4-OHT to induce cohesin depletion. Three biological replicates were collected and RNA was extracted. Microarray samples were prepared following the manufacturers instructions (Affymetrix) using 200ng of total RNA. Microarry samples were hybridized to Affymetrix GeneChip Mouse Gene 1.0 ST Arrays and the analysis was performed using the Bioconductor Package for R.
2015-02-19 | E-GEOD-62325 | biostudies-arrayexpress