Abstract
Relevance: Double-strand DNA breaks and replication-associated lesions are highly cytotoxic forms of genomic damage that contribute to carcinogenesis and telomere instability and influence tumor responses to radiation and chemotherapy. Apollo nuclease (DCLRE1B/SNM1B) is a 5’-3’ exonuclease involved in interstrand cross-link repair, replication stress response, and telomere maintenance through TRF2-dependent recruitment.The study aimed to systematize current knowledge on the structural and biochemical properties of Apollo, its role in the DNA damage response and telomere biology, and the contributions of pathogenic variants and altered DCLRE1B expression to carcinogenesis.Materials and Methods: A structured literature search was conducted across PubMed, Scopus, Web of Science, and Google Scholar, covering the period 2015-2025. Experimental, structural, cellular, and clinical studies investigating DCLRE1B function, mutations, and expression patterns were included in the analysis.Results: Structural analyses demonstrate that Apollo functions as a 5'→3’ exonuclease with a conserved metallo-β-lactamase/β-CASP core and a specialized DNA-binding groove, explaining its limited processivity and substrate specificity. Apollo localizes to telomeres via TRF2 and is required for proper processing of leading-strand telomeres, preventing chromosome end fusions mediated by non-homologous end joining (NHEJ). Loss of Apollo leads to telomere dysfunction, chromosomal instability, and hypersensitivity to ionizing radiation and interstrand cross-linking agents. Pan-cancer transcriptomic analyses further reveal dysregulation of DCLRE1B expression, which correlates with clinical prognosis, tumor immune microenvironment features, and response to immunotherapy.Conclusion: Apollo is a multifunctional nuclease that links telomere maintenance, replication stress, and interstrand cross-link repair. Evaluation of DCLRE1B status may contribute to cancer risk assessment and personalization of DNA damage-based therapy.