DCLRE1A encodes a DNA repair nuclease that functions as a 5'-to-3' exonuclease in multiple DNA damage repair processes 1. The protein primarily contributes to interstrand cross-link (ICL) repair, with DCLRE1A-deficient cells showing hypersensitivity to ICL-inducing agents like mitomycin C and cisplatin 1. DCLRE1A works in conjunction with XPF-ERCC1 in the 'unhooking' step of ICL repair and interacts with other genome integrity proteins including PCNA 1. Beyond canonical ICL repair, DCLRE1A protects mitochondrial homeostasis by alleviating mtDNA oxidative damage and mitochondrial dysfunction, particularly in lens epithelial cells where it prevents age-related cataract formation 2 3. The protein's expression is regulated through ubiquitin-mediated degradation by the E3 ligase SYVN1 2. Clinical significance includes associations with cancer progression, where DCLRE1A expression levels correlate with treatment response in colorectal cancer 4 and genetic variants may influence chemotherapy toxicity 5. The gene is also identified as a potential breast cancer predisposition candidate 6 and prognostic biomarker in ovarian cancer 7.