The Cancer/Testes (CT) Antigen HORMAD1 is germ cell-restricted and plays developmental roles in generation and processing of meiotic DNA Double Strand Breaks (DSB). Many tumors aberrantly overexpress HORMAD1 yet the potential impact of this CT antigen on cancer biology is unclear. We tested a potential role of HORMAD1 in genome maintenance in lung adenocarcinoma cells. We show that HORMAD1 re-distributes to nuclear foci and co-localizes with the DSB marker γH2AX in response to ionizing radiation (IR) and chemotherapeutic agents. The HORMA domain and C-term disordered oligomerization motif are necessary for localization of HORMAD1 to IR-induced foci (IRIF). HORMAD1-depleted cells are sensitive to IR and camptothecin. In reporter assays, Homologous Recombination (HR)-mediated repair of targeted ISce1-induced DSBs is attenuated in HORMAD1-depleted cells. In Non-Homologous End Joining (NHEJ) reporter assays, HORMAD1-depletion does not affect repair of ISce1-induced DSB. Early DSB signaling events (including ATM phosphorylation and formation of γH2AX, 53BP1 and NBS1 foci) are intact in HORMAD1-depleted cells. However, generation of RPA-ssDNA foci and redistribution of RAD51 to DSB are compromised in HORMAD1-depleted cells, suggesting that HORMAD1 promotes DSB resection. HORMAD1-mediated HR is a neomorphic activity that is independent of its meiotic partners (including HORMAD2 and CCDC36. Bioinformatic analysis of TCGA data show that similar to known HR pathway genes HORMAD1 is overexpressed in lung adenocarcinomas. Overexpression of HR genes is associated with specific mutational profiles (including copy number variation). Taken together, we identify HORMAD1-dependent DSB repair as a new mechanism of radioresistance and a probable determinant of mutability in lung adenocarcinoma.

中文翻译：

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癌症/睾丸激素（CT）抗原HORMAD1促进肺腺癌细胞中的同源重组DNA修复和放射抗性。

癌症/睾丸激素（CT）抗原HORMAD1受生殖细胞限制，在减数分裂DNA双链断裂（DSB）的产生和加工中起发展作用。许多肿瘤异常表达HORMAD1，但尚不清楚此CT抗原对癌症生物学的潜在影响。我们测试了HORMAD1在肺腺癌细胞的基因组维持中的潜在作用。我们显示，HORMAD1重新分布到核病灶，并与DSB标记γH2AX共同定位，以响应电离辐射（IR）和化学治疗剂。HORMA域和C端无序的寡聚化基序对于将HORMAD1定位到IR诱导灶（IRIF）是必需的。耗尽HORMAD1的细胞对IR和喜树碱敏感。在记者分析中，同源重组（HR）介导的靶向ISce1诱导的DSBs修复在HORMAD1缺失的细胞中减弱。在非同源末端连接（NHEJ）报告基因检测中，HORMAD1耗竭不会影响ISce1诱导的DSB的修复。在耗尽HORMAD1的细胞中，早期的DSB信号事件（包括ATM磷酸化和γH2AX，53BP1和NBS1病灶的形成）完好无损。但是，在HORMAD1缺失的细胞中，RPA-ssDNA病灶的生成和RAD51向DSB的重新分布受到损害，这表明HORMAD1促进了DSB切除。HORMAD1介导的HR是一种新态活动，独立于它的减数分裂伙伴（包括HORMAD2和CCDC36）。TCGA数据的生物信息学分析表明，与已知的HR通路基因类似，HORMAD1在肺腺癌中过表达。HR基因的过表达与特定的突变谱（包括拷贝数变异）有关。两者合计，我们确定依赖HORMAD1的DSB修复是一种新的放射抗性机制，并可能是肺腺癌变异性的决定因素。