CDC6 (cell division cycle 6) is a critical licensing factor essential for initiating DNA replication in eukaryotic cells. Mechanistically, CDC6 functions as a co-loader protein that works with the origin recognition complex (ORC) and CDT1 to deposit the MCM2-7 replicative helicase onto DNA as a head-to-head double hexamer, thereby licensing replication origins during G1 phase 1. This process marks origins for duplication during S phase and establishes pre-replicative complexes (pre-RCs) 1. CDC6 also participates in checkpoint controls ensuring DNA replication completes before mitosis begins 1. Clinically, CDC6 dysfunction causes Meier-Gorlin syndrome (MGS), a rare autosomal recessive primordial dwarfism characterized by microtia, patellar anomalies, and growth retardation; CDC6 mutations account for a portion of the ~67-78% of MGS cases attributed to pre-replication complex gene mutations 2. Beyond its canonical replication function, CDC6 emerges as a significant oncogenic biomarker. High CDC6 expression correlates with poor overall survival in glioma patients and associates with markers of aggressive disease 3. CDC6 stability is regulated by deubiquitination via OTUD6A; the OTUD6A-CDC6 axis promotes tumor progression and chemoresistance 4. Additionally, CDC6 in tumor cells orchestrates fibroblast senescence via TGF-β1 secretion, reprogramming the tumor microenvironment and modulating immunotherapy response 5. Impaired CDC6 function confers resistance to PARP inhibition in BRCA2-deficient prostate cancer 6.