Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA553571 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency
| PRJNA553208 | ENA
Project description: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.
2019-12-23 | GSE133954 | GEO
Project description:Copy-number variation by Comparative Genomic Hybridization (CGH) on thymocytes and Kidney (control) of Tdp2+/+Atm-/- and Tdp2-/-Atm-/- mice.
2019-12-23 | GSE134054 | GEO
Project description:The ATM kinase is a master regulator of the DNA damage response to double-strand breaks (DSBs) and a well-established tumour suppressor whose loss is the cause of the neurodegenerative and cancer-prone syndrome Ataxia-Telangiectasia (A-T). A-T patients and Atm-/- mouse models are particularly predisposed to develop lymphoid cancers derived from deficient repair of RAG-induced DSBs during V(D)J recombination. 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 increases the incidence of thymic tumours in Atm-/- mice. Furthermore, we find that TOP2 strongly colocalizes with RAG, both genome-wide and at V(D)J recombination sites, resulting in an increased endogenous chromosomal fragility of these regions. Thus, our findings demonstrate a strong causal relationship between endogenous TOP2-induced DSBs and cancer development, confirming these lesions as major drivers of ATM-deficient lymphoid malignancies, and potentially other conditions and cancer types.
| S-EPMC7021672 | biostudies-literature
Project description:To find genes deregulated in the pathogenisis of T-cells in Atm deficient mice, we performed expression profiling of Atm deficient thymic lymphomas, wildtype thymi and Atm deficient thymi without macroscopic enlargement, representing an intermediate stage in the process of tumorigenisis. Keywords: genetic modification, disease state analysis
2008-07-15 | GSE10807 | GEO
Project description:ATM gene mutation carriers are predisposed to estrogen receptor (ER)-positive breast cancer (BC). ATM prevents BC oncogenesis by activating p53 in every cell; however, much remains unknown about tissue-specific oncogenesis following ATM loss. Here, we report that ATM controls the early transcriptional response to estrogens. This response depends on topoisomerase II (TOP2), which generates TOP2-DNA double-strand break (DSB) complexes and rejoins the breaks. When TOP2-mediated ligation fails, ATM facilitates DSB repair. Following estrogen exposure, TOP2-dependent DSBs arise at the c-MYC enhancer in human BC cells, and their defective repair changes the activation profile of enhancers and induces the overexpression of many genes including the c-MYC oncogene. CRISPR/Cas9 cleavage at the enhancer also causes c-MYC overexpression, indicating that this DSB causes c-MYC overexpression. Estrogen treatment induced c-Myc protein overexpression in mammary epithelial cells of ATM-deficient mice. In conclusion, ATM suppresses the c-Myc-driven proliferative effects of estrogens, possibly explaining such tissue-specific oncogenesis.
2023-06-01 | GSE218320 | GEO
Project description:In depth analysis of double strand break signaling was performed using mouse Pre-B cells and Human HCT116 cells. Our analysis included the induction of double strand breaks with ionizing radiation with the addition of ATM and DNA-PKcs inhibitors, alone and in combination.
2024-10-17 | PXD042258 | Pride
Project description:DNA Double Strand Breaks (DSBs) are harmful lesions that require rapid detection and repair in order to avoid toxic genomic rearrangements. DSBs elicit the so called DNA Damage Response (DDR), largely relying on ataxia telangiectasia mutated (ATM) and DNA Protein Kinase (DNAPK), two members of the PI3K-like kinase family, whose respective functions during the sequential steps of the DDR remains controversial. Using the DIvA cell line, expressing the AsiSI restriction enzyme, we have investigated the role of ATM and DNAPK in several aspects of the DDR upon induction of multiple clean DSBs throughout the human genome. High resolution mapping revealed that they are activated and spread in cis on a confined region surrounding all DSBs, independently of the pathway used for repair. However, a thorough analysis of repair kinetics, H2AX domain establishment and H2AX foci structure and dynamics revealed non overlapping functions for the two kinases once recruited at DSBs. Our results suggest that ATM is not solely acting on chromatin marks but also on chromatin organisation in order to ensure repair accuracy and survival.
2015-09-30 | E-MTAB-2992 | biostudies-arrayexpress
Project description:Doxorubicin is a widely used chemotherapeutic drug that intercalates between DNA base-pairs and posions Topoisomerase II, although the mechanistic basis for cell killing remains speculative. Here we show that both anthracyclines and Topoisomerase II poison cause enhanced DNA double-strand breaks around CpG island promoters of active genes genome-wide. We propose that torsion-based enhancement of nucleosome turnover exposes promoter DNA, ultimately causing DNA breaks around promoters that contributes to cell killing. We have analyzed mouse squamous cell carcinoma cells treated with doxorubicin, aclarubicin and etoposide. The direct in situ Breaks Labeling, Enrichment on Streptavidin (BLESS, PMID 23503052) method was used for mapping DNA double-strand breaks genome-wide.
2015-01-31 | E-GEOD-62927 | biostudies-arrayexpress
Project description:RNA sequencing of Mus musculus thymic lymphomas [ATM and RAG2]
| PRJNA498287 | ENA