Abstract

HCF-1 is a highly conserved and abundant chromatin-associated host cell factor required for transcriptional activation of herpes simplex virus immediate-early genes by the virion protein VP16. HCF-1 exists as a heterodimeric complex of associated N- (HCF-1_N) and C- (HCF-1_C) terminal subunits that result from proteolytic processing of a precursor protein. We have used small-interfering RNA (siRNA) to inactivate HCF-1 in an array of normal and transformed mammalian cells to identify its cellular functions. Our results show that HCF-1 is a broadly acting regulator of two stages of the cell cycle: exit from mitosis, where it ensures proper cytokinesis, and passage through the G₁ phase, where it promotes cell cycle progression. Proteolytic processing is necessary to separate and ensure these two HCF-1 activities, which are performed by separate HCF-1 subunits: the HCF-1_N subunit promotes passage through the G₁ phase whereas the HCF-1_C subunit is involved in proper exit from mitosis. These results suggest that HCF-1 links the regulation of exit from mitosis and the G₁ phase of cell growth, possibly to coordinate the reactivation of gene expression after mitosis.