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HiNF-P Directly Links the Cyclin E/CDK2/p220^NPAT Pathway to Histone H4 Gene Regulation at the G₁/S Phase Cell Cycle Transition

Angela Miele,^1, Corey D. Braastad,^1, William F. Holmes,^1, Partha Mitra,^1, Ricardo Medina,^1, Ronglin Xie,^1, Sayyed K. Zaidi,¹ Xin Ye,² Yue Wei,³ J. Wade Harper,² Andre J. van Wijnen,¹ Janet L. Stein,¹ and Gary S. Stein^1*

Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts 01655,¹ Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,² Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030³

Received 18 March 2005/ Accepted 5 April 2005

Genome replication in eukaryotic cells necessitates the stringent coupling of histone biosynthesis with the onset of DNA replication at the G₁/S phase transition. A fundamental question is the mechanism that links the restriction (R) point late in G₁ with histone gene expression at the onset of S phase. Here we demonstrate that HiNF-P, a transcriptional regulator of replication-dependent histone H4 genes, interacts directly with p220^NPAT, a substrate of cyclin E/CDK2, to coactivate histone genes during S phase. HiNF-P and p220 are targeted to, and colocalize at, subnuclear foci (Cajal bodies) in a cell cycle-dependent manner. Genetic or biochemical disruption of the HiNF-P/p220 interaction compromises histone H4 gene activation at the G₁/S phase transition and impedes cell cycle progression. Our results show that HiNF-P and p220 form a critical regulatory module that directly links histone H4 gene expression at the G₁/S phase transition to the cyclin E/CDK2 signaling pathway at the R point.

These authors contributed equally.

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