Mechanism and potential therapeutic strategies of genetic abnormalities involved in deoxyribonucleic acid double-strand breaks leading to the development of human non-obstructive azoospermia.

BACKGROUND: Non-obstructive azoospermia (NOA) is a testicular or pre-testicular spermatogenic disorder characterized by severe impairment in sperm production due to testicular dysfunction. Whole-exome sequencing has identified mutations in several genes related to double-strand break (DSB) formation and repair in patients with NOA. In this review, we aimed to comprehensively elucidate the relationship between DSB formation and repair-related gene abnormalities, and NOA occurrence. METHODS: This review summarizes current knowledge on the role of DSB-related gene mutations in NOA, focusing on their functions in meiotic recombination and deoxyribonucleic acid repair pathways. RESULTS: Programmed formation of DSB is a key step in meiosis, initiating recombination and exchange between homologous chromosomes to ensure accurate transmission of genetic material. Under normal conditions, DSBs are generated during meiosis in spermatocytes, and their repair primarily involves homologous recombination, non-homologous end-joining, and single-strand annealing. Abnormalities in genes regulating DSB formation or repair disrupt meiosis, impair spermatogenesis, and induce the occurrence of NOA. CONCLUSION: This review highlights the association between DSB formation and repair gene abnormalities and the pathogenesis of NOA. In addition, we summarize the therapeutic potential of targeting DSB repair-related pathways, providing new insights into the mechanisms and treatment strategies for NOA.