DNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have dire consequences as damaged DNA can result in cells turning cancerous. Here we compare germline and somatic variants in DDR genes, specifically looking at their locations in the corresponding three-dimensional (3D) structures, Pfam domains, and protein-protein interaction interfaces. We show that somatic variants are more likely to be found in Pfam domains and protein interaction interfaces than are pathogenic germline variants or variants of unknown significance (VUS). We also show that there are hotspots in the structures of ATM and BRCA2 proteins where pathogenic germline, and recurrent somatic variants from primary and metastatic tumours, cluster together in 3D. Moreover, in the ATM, BRCA1 and BRCA2 genes from prostate cancer patients, the distributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam domains. Together, these results provide a better characterisation of the most recurrent affected regions in DDRs and could help in the understanding of individual susceptibility to tumour development.

中文翻译：

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影响DDR机制的种系和体细胞变异的计算和结构分析，及其对人类疾病和前列腺癌进展的影响

DNA损伤反应（DDR）蛋白对于通过识别和修复DNA中的错误来维持基因组完整性至关重要。影响其功能的变异体可能会带来可怕的后果，因为受损的DNA可能导致细胞癌变。在这里，我们比较DDR基因中的种系和体细胞变体，特别是查看它们在相应的三维（3D）结构，Pfam域和蛋白质-蛋白质相互作用界面中的位置。我们表明，体细胞变异体比致病性生殖系变异体或未知意义（VUS）变异体更有可能在Pfam域和蛋白质相互作用界面中发现。我们还显示，ATM和BRCA2蛋白的结构中存在热点，其中病原体种系以及来自原发性和转移性肿瘤的复发性体细胞变异以3D形式聚集在一起。此外，在来自前列腺癌患者的ATM，BRCA1和BRCA2基因中，良性，病原性，VUS和复发性体细胞变异的种系分布在整个Pfam域中都不同。总之，这些结果可以更好地表征DDRs中最常见的患病区域，并有助于了解个体对肿瘤发展的敏感性。