GMNN (geminin) is a critical negative regulator of DNA replication that prevents genomic instability by inhibiting replication initiation. During G1 phase, GMNN binds to and inactivates CDT1, preventing the incorporation of MCM2-7 replicative helicases into pre-replication complexes 1. Additionally, GMNN inhibits the histone acetyltransferase activity of KAT7/HBO1 in a CDT1-dependent manner, further suppressing DNA replication licensing and histone H4 acetylation [UniProt annotation]. GMNN also functions as a transcriptional regulator, repressing Hox protein activity to coordinate cell proliferation control [UniProt annotation]. Cell-cycle regulation of GMNN is precise: the protein accumulates during G1/S phases and is degraded at the metaphase-anaphase transition, allowing re-licensing of origins for the subsequent cell cycle [UniProt annotation]. Pathological mutations in GMNN cause Meier-Gorlin syndrome 6 and female infertility characterized by preimplantation embryo arrest. Recently, rare missense mutations were identified in infertile women that impaired GMNN-CDT1 binding, resulting in DNA re-replication, CHK1 activation, and cell cycle disturbance 2. In hepatocellular carcinoma, GMNN is upregulated and serves as a biomarker for microvascular invasion and adverse prognosis 3, suggesting dysregulation contributes to cancer progression.