Regulation of cyclin D1-dependent kinase activity is essential for cell cycle progression and DNA replication fidelity. Critically, impaired cyclin D1 phosphorylation and ubiquitin-mediated proteolysis following the G1/S transition drives neoplastic growth, suggesting that posttranslational regulation is required for cell homeostasis. Elucidation of mechanisms facilitating S-phase cyclin D1 accumulation and novel functions of nuclear cyclin D1/CDK4 kinase is critical for understanding the role of cyclin D1 in tumorigenesis. The work presented herein demonstrates that accelerated, Fbx4-dependent cyclin D1 degradation following S-phase DNA damage is essential to maintain genome stability. Furthermore, Fbx4 functions as a bona fide tumor suppressor, as Fbx4-deficient mice develop spontaneous tumors and murine fibroblasts exhibit cyclin D1 stabilization, nuclear accumulation, and associated genomic instability. This work also describes novel regulation of the PRMT5 methyltransferase by nuclear cyclin D1/CDK4, thereby facilitating histone methylation and gene repression during S-phase necessary for neoplastic growth. Finally, current work reveals a synergistic relationship between constitutively nuclear cyclin D1 and impaired DNA damage checkpoint integrity in driving lymphomagenesis in mice. Collectively, these findings define an intricate relationship wherein nuclear cyclin D1/CDK4 activity modulates genetic alterations necessary for perturbed DNA replication, genomic instability, and ultimately neoplasia.