Defective DNA Repair: A Putative Nexus Linking Immunological Diseases, Neurodegenerative Disorders, and Cancer.

Abstract

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 aging. 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 leading to the divergent consequences. It is important to discover the switch(es) that direct further the pathogenic process either to proliferative, or degenerative diseases. Our understanding the influence of DNA damage on diverse human disorders may enable a 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 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.