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Series GSE45625 Query DataSets for GSE45625
Status Public on Mar 30, 2013
Title mSWI/SNF (BAF) Complexes Facilitate Decatentation of DNA by Topoisomerase IIa
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Recent exon sequencing studies of human tumors have revealed that subunits of mSWI/SNF or BAF complexes are mutated in more than 20% of human malignancies, yet the mechanisms involved in tumor suppression is unclear. BAF chromatin remodeling complexes are polymorphic assemblies that use energy provided by ATP hydrolysis to regulate transcription through the control of chromatin structure and the placement of Polycomb (PcG) across the genome. Several proteins dedicated to this large multi-subunit complex, including SMARCA4 (BRG1) and BAF250A (ARID1A), are mutated at frequencies similar to that of many recognized tumor suppressors. In particular, the core ATPase BRG1 is mutated in 5-10% of childhood medulloblastoma (MB) and greater than 15% of Burkitt's Lymphoma (BL). Here we find a novel function of BAF complexes in decatenating newly replicated sister chromatids, which is necessary for proper chromosome segregation during mitosis. We find that deletion of Brg1, as well as the expression of Brg1 point mutants identified in human tumors leads to anaphase bridge formation (sister chromatids linked by catenated strands of DNA), and a G2/M phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes directly interact with endogenous TopoIIα through BAF250a and are required for TopoIIα binding to about 12,000 sites over the genome. Our results indicate that TopoIIα’s chromatin binding is dependent on the ATPase activity of Brg1, which is compromised in oncogenic Brg1 mutants. These studies indicate that the ability of TopoIIα to prevent DNA entanglement at mitosis requires BAF complexes and suggest that this activity contributes to the role of BAF subunits as tumor suppressors.
Overall design Examination of sites of TopoIIa activity in WT and Brg1-/- ES cells as defined by TopoIIa-DNA covalent adducts formed in the presence of etoposide
Contributor(s) Crabtree GR
Citation(s) 23698369
Submission date Mar 29, 2013
Last update date May 15, 2019
Contact name Emily Dykhuizen
Organization name Purdue University
Department medicinal chemistry and molecular pharmacology
Lab dykhuizen
Street address 201 S. University
City West Lafayette
State/province IN
ZIP/Postal code 47907
Country USA
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (4)
GSM1110842 V5-TopoIIa etoposide BrgWT
GSM1110843 V5-TopoIIa etoposide BrgKO
GSM1110844 input BrgWT
BioProject PRJNA195426
SRA SRP020246

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Supplementary file Size Download File type/resource
GSE45625_RAW.tar 310.0 Kb (http)(custom) TAR (of BED)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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