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| Status |
Public on Mar 13, 2018 |
| Title |
Effect of DNA bindng small molecules on SSRP1 genomic distribution |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Small molecules directly binding DNA in cells destabilized chromatin what is "sensed" by histone chaperone FACT. FACT binds regions with destabilized chromatin via "c-trapping".
DNA-targeting small molecules are widely used for anticancer therapy based on their ability to induce cell death, presumably via DNA damage. DNA in the eukaryotic cell is packed into chromatin, a highly-ordered complex of DNA, histones, and non-histone proteins. These agents perturb chromatin organization. However, the mechanisms, consequences, and impact of the alterations of chromatin structure in relation to their anti-cancer activity is unclear because it is difficult to separate DNA damage and chromatin damage in cells. We recently demonstrated that curaxins, small molecules with broad anticancer activity, bind DNA without causing detectable DNA damage by interfering with histone/DNA interactions and destabilizing the nucleosome. Chromatin unfolding caused by curaxins is sensed by histone chaperone FACT. FACT binds unfolded nucleosomes, which leads to chromatin trapping or c-trapping. In this study, we investigated whether other DNA-targeting small molecules disturb chromatin and cause c-trapping. We found that only compounds directly binding DNA induce chromatin damage and c-trapping. Chromatin damage may occur in the absence of DNA damage and is dependent on the mechanism of compound binding to DNA and its ability to bind chromatinized DNA in cells. We show that FACT is sensitive to a plethora of nucleosomes perturbations induced by DNA-binding small molecules, including displacement of the linker histone, eviction of core histones, and accumulation of negative supercoiling. Most importantly, the cytotoxicity of DNA-binding small molecules correlates with their ability to cause chromatin damage, but not DNA damage.
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| Overall design |
HT1080 cells were treated with 3uM of CBL0137, 0.3uM of CBL0100 or 3uM of aclacinomycin A for 1.5 hours
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| Contributor(s) |
Gurova K, Wang J |
| Citation(s) |
29339544, 32498018 |
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| Submission date |
Dec 01, 2017 |
| Last update date |
Jul 14, 2021 |
| Contact name |
Katerina Gurova |
| E-mail(s) |
katerina.gurova@roswellpark.org
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| Phone |
716-845-4760
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| Organization name |
Roswell Park Cancer Institute
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| Department |
Cell Stress Biology
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| Street address |
Elm and Carlton Str
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| City |
Buffalo |
| State/province |
NY |
| ZIP/Postal code |
14127 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (7)
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| Relations |
| BioProject |
PRJNA420688 |
| SRA |
SRP125953 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE107595_RAW.tar |
1007.5 Mb |
(http)(custom) |
TAR (of BED, BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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