XRCC3 is a critical component of the homologous recombination repair (HRR) pathway for double-strand DNA breaks. As a RAD51 paralog, XRCC3 interacts with RAD51 and functions within the CX3 complex downstream of RAD51 recruitment, binding to Holliday junctions and replication fork intersections to resolve recombination intermediates 1. XRCC3 deficiency reduces error-free homology-directed repair of DNA double-strand breaks 25-fold, demonstrating its essential role in preventing mutagenic or lethal DNA damage 1. The protein also regulates mitochondrial DNA copy number under oxidative stress and participates in telomere maintenance via recombination. XRCC3 polymorphisms show variable cancer associations across populations. The T241M variant increases hepatocellular carcinoma (HCC) risk, particularly among Asian populations and hepatitis B surface antigen-positive individuals 2, and confers increased bladder cancer risk for the C18067T polymorphism in Asians 3. The rs861539 A allele conversely reduces ovarian cancer risk through altered splicing regulation 4. However, no significant association exists between T241M and lung cancer risk across multiple ethnic groups 56. These findings suggest XRCC3's cancer relevance depends on specific genetic variants and population contexts, highlighting the importance of personalized risk assessment in cancer susceptibility screening.