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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Dec 23, 2019 |
| Title |
Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
The ATM kinase is a master regulator of the DNA damage response to double-strand breaks (DSBs) and a well-established tumour suppressor. Loss-of-function mutations in the gene are not only frequently found in many types of cancer, but constitute the underlying cause of the neurodegenerative and cancer-prone genetic syndrome Ataxia-Telangiectasia (A-T). A-T patients are particularly predisposed to develop lymphoid cancers, which are thought to arise from inefficient signalling and inaccurate repair of RAG-induced DSBs during V(D)J recombination, and which the Atm-/- mouse models recapitulate in the form of very aggressive T-cell malignancies. Here, we unexpectedly find that specifically disturbing the repair of DSBs produced by DNA topoisomerase II (TOP2) by genetically removing the highly specialised repair enzyme TDP2, strongly increases the incidence of thymic tumours in Atm-/- mice, but without changing their molecular characteristics or underlying genomic rearrangements, including a significant association with Tcr loci. Furthermore, we find that TOP2 strongly colocalizes with RAG, both in a genome-wide scale and specifically at sites undergoing V(D)J recombination, in a manner that is consistent with its involvement in solving topological problems associated to 3D genome organization, and which results in an increased chromosomal fragility of these regions. Thus, our findings demonstrate a strong causal relationship between accidental TOP2-induced DSBs and cancer development, putting forward these lesions as major drivers of the genome rearrangements that are characteristic of ATM-deficient lymphoid malignancies, and opening the door for their involvement in other conditions and cancer types.
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| Overall design |
TOP2B and TOP2A ChIPseq in mouse isolated thymocytes.
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| Contributor(s) |
Álvarez-Quilón A, Terrón-Bautista J, Delgado-Sainz I, Serrano-Benitez A, Romero-Granados R, Martínez-García PM, Bernal-Lozano C, Quintero C, García-Quintanilla L, Cortés-Ledesma F |
| Citation(s) |
32060399 |
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| Submission date |
Jul 08, 2019 |
| Last update date |
Mar 02, 2020 |
| Contact name |
Felipe Cortés Ledesma |
| E-mail(s) |
fcortes@cnio.es
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| Organization name |
CNIO
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| Department |
Molecular Oncology
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| Lab |
Topology and DNA breaks
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| Street address |
Melchor Fernández Almagro 3
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| City |
Madrid |
| State/province |
Madrid |
| ZIP/Postal code |
28029 |
| Country |
Spain |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA553208 |
| SRA |
SRP213684 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE133954_RAW.tar |
429.9 Mb |
(http)(custom) |
TAR (of BED, BIGWIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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