The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells.
The Cancer/Testes (CT) Antigen HORMAD1 promotes Homologous Recombinational DNA Repair and Radioresistance in Lung adenocarcinoma cells.
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癌症/睾丸（CT）抗原Hormad1促进肺腺癌细胞中的同源重组DNA修复和放射线。
DOI：
10.1038/s41598-018-33601-w
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发表时间：
2018-10-17
影响因子：
4.6
通讯作者：
Vaziri C
中科院分区：
文献类型：
--
作者：
Gao Y;Kardos J;Yang Y;Tamir TY;Mutter-Rottmayer E;Weissman B;Major MB;Kim WY;Vaziri C
肿瘤/睾丸（CT）抗原HORMAD1是生殖细胞限制性抗原，在减数分裂DNA双链断裂（DSB）的产生和加工中发挥发育作用。许多肿瘤异常过表达HORMAD1，但这种CT抗原对癌症生物学的潜在影响尚不清楚。我们测试了HORMAD1在肺腺癌细胞基因组维持中的潜在作用。我们发现，在电离辐射（IR）和化疗药物的作用下，HORMAD1重新分布到核病灶，并与DSB标记物γ - h2ax共定位。HORMA结构域和C-term无序寡聚基序是HORMAD1定位到ir诱导灶（IRIF）的必要条件。hormad1缺失的细胞对IR和喜树碱敏感。在报告者实验中，同源重组（HR）介导的isce1诱导的dsb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缺失不影响isce1诱导的DSB修复。在hormad1缺失的细胞中，早期DSB信号事件（包括ATM磷酸化和γH2AX、53BP1和NBS1灶的形成）是完整的。然而，在HORMAD1缺失的细胞中，RPA-ssDNA病灶的产生和RAD51向DSB的再分布受到损害，这表明HORMAD1促进了DSB的切除。hormad1介导的HR是一种独立于其减数分裂伙伴（包括HORMAD2和CCDC36）的新形态活性。TCGA数据的生物信息学分析显示，与已知的HR通路基因相似，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。综上所述，我们确定了hormad1依赖性DSB修复作为肺腺癌放射耐药的新机制和可能的突变决定因素。
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.
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