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| Status |
Public on Apr 26, 2019 |
| Title |
Topoisomerase II-induced Chromosome Breakage and Translocation Is Determined by Chromosome Architecture and Transcriptional Activity [Nascent RNA] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Topoisomerase II (TOP2) relieves torsional stress during transcription, DNA replication and chromosome segregation, by forming transient cleavage complex intermediates (TOP2ccs) that contain TOP2-linked DNA breaks. While TOP2ccs are normally reversible they can be ‘trapped’ by chemotherapeutic drugs such as etoposide, and subsequently converted into irreversible TOP2-linked DSBs that threaten genome stability. Here, using genomics approaches, we have quantified the etoposide-induced trapping of TOP2ccs, their conversion into irreversible TOP2-linked DSBs, and their processing during DNA repair genome-wide, as a function of time. We find that while TOP2 trapping is independent of transcription it requires pre-existing binding of cohesin to DNA. In contrast, the conversion of trapped TOP2ccs to irreversible DSBs during DNA repair is accelerated two-fold at transcribed loci, relative to non-transcribed loci. This conversion is dependent on proteasomal degradation and TDP2 phosphodiesterase activity. Quantitative modeling shows that only two critical features of pre-existing chromatin structure- namely, cohesin binding and transcriptional activity- can be used to accurately predict the kinetics of TOP2-induced DSBs. Thus, our study permits a mechanistic understanding of TOP2 induced genome instability.
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| Overall design |
Nascent RNA-seq profile in Abelson-transformed pre-B cell, upon treatment with DRB, IFNb, or not treated
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| Contributor(s) |
Canela A, Maman Y, Huang SN, Wutz G, Tang W, Zagnoli-Vieira G, Callen E, Wong N, Day A, Peters J, Caldecott KW, Pommier Y, Nussenzweig A |
| Citation(s) |
31202577 |
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| Submission date |
Apr 09, 2019 |
| Last update date |
Jan 29, 2020 |
| Contact name |
Yaakov Maman |
| Organization name |
Bar-Ilan University
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| Department |
Azrieli Faculty of Medicine
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| Lab |
Genome Instability & Cancer
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| Street address |
Henrietta Szold 8
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| City |
Safed |
| ZIP/Postal code |
1311502 |
| Country |
Israel |
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| Platforms (1) |
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| Samples (3) |
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| This SubSeries is part of SuperSeries: |
| GSE129529 |
Topoisomerase II-induced Chromosome Breakage and Translocation Is Determined by Chromosome Architecture and Transcriptional Activity |
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| Relations |
| BioProject |
PRJNA531666 |
| SRA |
SRP191552 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE129527_RAW.tar |
394.8 Mb |
(http)(custom) |
TAR (of BW) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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