Epigenetic inheritance in mammals relies in part on robust propagation of DNA methylation patterns throughout development. We show that the protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1), also known as NP95 in mouse and ICBP90 in human, is required for maintaining DNA methylation. UHRF1 colocalizes with the maintenance DNA methyltransferase protein DNMT1 throughout S phase. UHRF1 appears to tether DNMT1 to chromatin through its direct interaction with DNMT1. Furthermore UHRF1 contains a methyl DNA binding domain, the SRA (SET and RING associated) domain, that shows strong preferential binding to hemimethylated CG sites, the physiological substrate for DNMT1. These data suggest that UHRF1 may help recruit DNMT1 to hemimethylated DNA to facilitate faithful maintenance of DNA methylation.

Perturbations in the regulation of the core cell cycle machinery are frequently observed in human cancers. Cyclin D1 which functions as a mitogenic sensor and allosteric activator of CDK4/6, is one of the more frequently altered cell cycle regulators in cancers. Cyclin D1 is frequently overexpressed in cancers and its overexpression can be attributed to many factors including increased transcription, translation, and protein stability. Although cyclin D1 overexpression is clearly implicated in the affected cancers, overexpression of cyclin D1 is not sufficient to drive oncogenic transformation. Rather, emerging evidence suggests that nuclear retention of cyclin D1 resulting from altered nuclear trafficking and proteolysis is critical for the manifestation of its oncogenicity. This review provides a brief overview of current data documenting various mechanisms underlying aberrant cyclin D1 regulation in human cancers and their impact on neoplastic transformation.Work during the past two decades has provided a detailed molecular understanding of processes that drive cell cycle division. Early work resulted in the identification of the individual cyclin-dependent kinases that are activated during distinct cell cycle phases and contributed to our understanding of how phosphorylation of downstream targets in turn contributes to regulated cell cycle transitions. The recent generation of mice wherein individual cyclins or their cognate CDKs have been eliminated from the mouse germline has revealed the potential for significant redundancy with regard to CDK function and substrate regulation.While our fundamental understanding of the normal physiological functions of the cyclindependent kinase has increased dramatically, the potential pathological functions/activities remain to be established. This is particularly evident when one considers the potential contribution of G1 cyclins and CDKs to neoplastic transformation and growth. Regulation of G1 to S-phase progression is disrupted in nearly all cancers, due to its intimate function in the integration of growth factor signals with the cell cycle network. Of the G1 regulatory molecules, the cyclin D1/CDK4 complex is deregulated at a high frequency and is thought to contribute directly to neoplastic transformation and growth. Recent efforts have provided insights into the precise mechanisms whereby the cyclin D1-dependent kinase promotes tumorigenic growth and are discussed below.