A switch in mitotic histone H4 lysine 20 methylation status is linked to m phase defects upon loss of HCF-1

The abundant chromatin-associated human factor HCF-1 is a heterodimeric complex of HCF-1(N) and HCF-1(C) subunits that are essential for two stages of the cell cycle. The HCF-1(N) subunit promotes G1 phase progression, whereas the HCF-1(C) subunit ensures proper cytokinesis at completion of M phase. How the HCF-1(C) subunit functions is unknown. Here, we show that HCF-1(C) subunit depletion causes extensive mitotic defects, including a switch from monomethyl to dimethyl lysine 20 of histone H4 (H4-K20) and defective chromosome alignment and segregation. Consistent with these activities, the HCF-1 c subunit can associate with chromatin independently of the HCF-1N subunit and regulates the expression of the H4-K20 methyltransferase PR-Set7. Indeed, upregulation of PR-Set7 expression upon loss of HCF-1 leads to improper mitotic H4-K20 methylation and cytokinesis defects. These results establish the HCF-1(C) subunit as an important M phase regulator and suggest that H4-K20 methylation status contributes to chromosome behavior during mitosis and proper cytokinesis.