Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency.,Nature Communications

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Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency.
Nature Communications ( IF 14.7 ) Pub Date : 2020-02-14 , DOI: 10.1038/s41467-020-14638-w
Alejandro Álvarez-Quilón _{1,

2} , José Terrón-Bautista ₁ , Irene Delgado-Sainz ₁ , Almudena Serrano-Benítez ₁ , Rocío Romero-Granados ₁ , Pedro Manuel Martínez-García ₁ , Silvia Jimeno-González ₁ , Cristina Bernal-Lozano ₁ , Cristina Quintero ₁ , Lourdes García-Quintanilla ₁ , Felipe Cortés-Ledesma _{1,

3}

Affiliation

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.

中文翻译：

内源性拓扑异构酶II介导的DNA断裂驱动与ATM缺乏有关的胸腺癌易感性。

ATM激酶是对双链断裂（DSB）的DNA损伤反应的主要调节剂，也是成熟的肿瘤抑制因子，其抑制作用是神经退行性和癌症易感性共济失调-毛细血管扩张症（AT）的原因。AT患者和Atm-/-小鼠模型特别容易发展为在V（D）J重组过程中RAG诱导的DSB修复不足而引起的淋巴样癌。在这里，我们出乎意料地发现，通过遗传去除高度专业化的修复酶TDP2来特异性干扰DNA拓扑异构酶II（TOP2）产生的DSB的修复会增加Atm-/-小鼠胸腺肿瘤的发病率。此外，我们发现TOP2与RAG在整个基因组范围内以及在V（D）J重组位点上都强烈共定位，从而导致这些区域的内源染色体脆性增加。从而，

更新日期：2020-02-14

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