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| Status |
Public on Feb 20, 2020 |
| Title |
Suppressing Proteasome Mediated Processing of Topoisomerase II DNA-Protein Adducts Preserves Genome Integrity |
| Organism |
Mus musculus |
| Experiment type |
Other
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| Summary |
Here, we utilize high-resolution mapping of ETO-induced TOP2 lesions genome-wide (END-seq) (Canela et al., 2016), to examine the impact of proteasome inhibition on the fate of TOP2ccs. We found that once ETO-stabilized TOP2ccs had been proteolytically processed throughout the genome, and a robust DDR had been initiated, the large number of newly generated protein-free DSBs were repaired in a highly error-prone manner, resulting in toxic chromosomal translocations and rearrangements that lead to cell death. Notably, mis-repair of ETO-induced lesions occurred independently of the classical NHEJ or HR pathways. By inhibiting proteasome-mediated degradation of TOP2ccs either through chemical inhibition or by ablation of the ubiquitination of TOP2ccs by RNF4, an intact and enzymatically competent TOP2 was able to re-seal the protein-linked DSBs without invoking a significantly DDR. As a result, cells were protected from genomic instability, which ultimately led to enhanced cell survival after treatment with topoisomerase poisons.
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| Overall design |
END-seq profiles in B-cells treated with etoposide and proteasome inhibitor
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| Contributor(s) |
Sciascia N, Wu W, Zong D, Sun Y, Wong N, Wangsa D, John S, Ried T, Bunting S, Pommier Y, Nussenzweig A |
| Citation(s) |
32057297 |
| Submission date |
Nov 14, 2019 |
| Last update date |
Feb 23, 2020 |
| Contact name |
Wei Wu |
| Organization name |
National Cancer Institute
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| Department |
Center for Cancer Research
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| Lab |
Laboratory of Genome Integrity
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| Street address |
9000 Rockville Pike
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| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
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| Platforms (1) |
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| Samples (35)
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| Relations |
| BioProject |
PRJNA589537 |
| SRA |
SRP229952 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE140372_RAW.tar |
2.7 Gb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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