Andarawi Safaa, Vodickova Ludmila, Uttarilli Anusha, Hanak Petr, Vodicka Pavel
Department of the Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 00 Prague, Czech Republic.
Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655/77, 32300 Pilsen, Czech Republic.
Mutagenesis. 2025 Mar 15;40(1):4-19. doi: 10.1093/mutage/geae029.
DNA damage is a common event in cells, resulting from both internal and external factors. The maintenance of genomic integrity is vital for cellular function and physiological processes. The inadequate repair of DNA damage results in the genomic instability, which has been associated with the development and progression of various human diseases. Accumulation of DNA damage can lead to multiple diseases, such as neurodegenerative disorders, cancers, immune deficiencies, infertility, and ageing. This comprehensive review delves the impact of alterations in DNA damage response genes (DDR) and tries to elucidate how and to what extent the same traits modulate diverse major human diseases, such as cancer, neurodegenerative diseases, and immunological disorders. DDR is apparently the trait connecting important complex disorders in humans. However, the pathogenesis of the above disorders and diseases are different and lead to divergent consequences. It is important to discover the switch(es) that direct further the pathogenic process either to proliferative, or degenerative diseases. Our understanding of the influence of DNA damage on diverse human disorders may enable the development of the strategies to prevent, diagnose, and treat these diseases. In our article, we analysed publicly available GWAS summary statistics from the NHGRI-EBI GWAS Catalog and identified 12 009 single-nucleotide polymorphisms (SNPs) associated with cancer. Among these, 119 SNPs were found in DDR pathways, exhibiting significant P-values. Additionally, we identified 44 SNPs linked to various cancer types and neurodegenerative diseases (NDDs), including four located in DDR-related genes: ATM, CUX2, and WNT3. Furthermore, 402 SNPs were associated with both cancer and immunological disorders, with two found in the DDR gene RAD51B. This highlights the versatility of the DDR pathway in multifactorial diseases. However, the specific mechanisms that regulate DDR to initiate distinct pathogenic processes remain to be elucidated.
DNA损伤是细胞中的常见事件，由内部和外部因素共同导致。基因组完整性的维持对于细胞功能和生理过程至关重要。DNA损伤修复不足会导致基因组不稳定，这与多种人类疾病的发生和发展相关。DNA损伤的积累可引发多种疾病，如神经退行性疾病、癌症、免疫缺陷、不育症和衰老。这篇综述深入探讨了DNA损伤反应基因（DDR）改变的影响，并试图阐明相同特征如何以及在何种程度上调节多种主要人类疾病，如癌症、神经退行性疾病和免疫紊乱。DDR显然是连接人类重要复杂疾病的特征。然而，上述疾病的发病机制各不相同，会导致不同的后果。发现引导致病过程进一步发展为增殖性疾病或退行性疾病的开关非常重要。我们对DNA损伤对多种人类疾病影响的理解可能有助于制定预防、诊断和治疗这些疾病的策略。在我们的文章中，我们分析了来自NHGRI-EBI全基因组关联研究（GWAS）目录的公开可用GWAS汇总统计数据，确定了12009个与癌症相关的单核苷酸多态性（SNP）。其中，119个SNP位于DDR途径中，具有显著的P值。此外，我们确定了44个与各种癌症类型和神经退行性疾病（NDD）相关的SNP，包括位于DDR相关基因ATM、CUX2和WNT3中的4个。此外，402个SNP与癌症和免疫紊乱都相关，其中2个位于DDR基因RAD51B中。这突出了DDR途径在多因素疾病中的多功能性。然而，调节DDR以启动不同致病过程的具体机制仍有待阐明。
