Background: Interindividual radiosensitivity is largely driven by genetic regulation of DNA damage recognition, repair, and cell-cycle control. TP53 and CDKN1A (p21) are key genomic markers associated with differential responses to ionizing radiation. Methods: This study investigated eight functional SNP markers across several key genes involved in DNA damage responses and cellular stress regulation, including TP53, CDKN1A/p21, APC, VEGF, XPD, and RAD51, in occupational groups exposed to chronic low-dose ionizing radiation at the Stepnogorsk Mining Chemical Combine and the Balkashinskoye uranium deposit. Genotyping was performed using PCR-based assays followed by restriction fragment length polymorphism (RFLP) analysis. Allele and genotype frequencies were compared between radiation-exposed workers and matched controls within Kazakh and Russian ethnic subgroups. Statistical differences were assessed using χ² tests, and associations with radioresistance were interpreted based on established functional characteristics of each polymorphism. Results: Four SNPs showed significant allele and genotype frequency shifts in radiation-exposed populations. The TP53 intron 3 insertion allele, TP53 intron 6 A allele, TP53 Pro72 (C) allele, and p21 codon 31 A allele were consistently enriched among exposed individuals. The strongest deviations were observed in Russian workers from Stepnogorsk (p < 0.01). These alleles are functionally associated with enhanced DNA repair efficiency, modified apoptotic responses, and strengthened cell-cycle checkpoint regulation. Conclusions: Significant enrichment of radioresistance-associated TP53 and CDKN1A (p21) variants was observed in uranium industry workers chronically exposed to low-to-moderate ionizing radiation. The observed patterns support a polygenic model of adaptive responses and emphasize the importance of genetic background in determining individual radiosensitivity under occupational exposure conditions.