Abstract
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.
Highlights
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)
Considering the strong sensitivity and repair defect of Tdp2−/− Atm−/− double-deficient cells to TOP2-induced DSBs33, we decided to address the physiological impact of these lesions in the context of the entire organism
TOP2B genome-wide binding correlates with sites of endogenous DSB accumulation (Fig. 5), and endogenous TOP2B-blocked lesions accumulate in Tdp2−/−Atm−/− thymocytes (Fig. 7)
Summary
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). Aberrant V(D)J recombination, is unlikely to represent the single driver of oncogenic translocations, as evidenced by additional V(D)J-unrelated regions of instability, and the persistent cancer predisposition observed upon RAG deficiency[16,17] These results strongly suggest additional sources of DSBs as relevant contributors to the ATM-deficient oncogenic translocations responsible for T-cell cancer predisposition. In this sense, aberrant action of DNA topoisomerase II (TOP2) can constitute an important source of chromosomal breakage[18]. Compounds present in the diet and the environment and some forms of pre-existing DNA damage, such as nicks or abasic sites, can poison TOP2 activity[18]
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