The histone gene activator HINFP is a nonredundant cyclin E/CDK2 effector during early embryonic cell cycles
Department of Cancer Biology; Department of Cell Biology
Animals; Blastocyst; Blotting, Western; Cell Cycle; Cell Cycle Proteins; Cells, Cultured; Cyclin E; Cyclin-Dependent Kinase 2; Embryo, Mammalian; Female; Fibroblasts; G1 Phase; Gene Expression Regulation, Developmental; Histones; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; S Phase; Signal Transduction; Time Factors
Cancer Biology | Cell Biology | Life Sciences | Medicine and Health Sciences
Competency for DNA replication is functionally coupled to the activation of histone gene expression at the onset of S phase to form chromatin. Human histone nuclear factor P (HiNF-P; gene symbol HINFP) bound to its cyclin E/cyclin-dependent kinase 2 (CDK2) responsive coactivator p220(NPAT) is a key regulator of multiple human histone H4 genes that encode a major subunit of the nucleosome. Induction of the histone H4 transcription factor (HINFP)/p220(NPAT) coactivation complex occurs in parallel with the CDK-dependent release of pRB from E2F at the restriction point. Here, we show that the downstream CDK-dependent cell cycle effector HINFP is genetically required and, in contrast to the CDK2/cyclin E complex, cannot be compensated. We constructed a mouse Hinfp-null mutation and found that heterozygous Hinfp mice survive, indicating that 1 allele suffices for embryogenesis. Homozygous loss-of-function causes embryonic lethality: No homozygous Hinfp-null mice are obtained at or beyond embryonic day (E) 6.5. In blastocyst cultures, Hinfp-null embryos exhibit a delay in hatching, abnormal growth, and loss of histone H4 gene expression. Our data indicate that the CDK2/cyclin E/p220(NPAT)/HINFP/histone gene signaling pathway at the G1/S phase transition is an essential, nonredundant cell cycle regulatory mechanism that is established early in embryogenesis.
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Citation: Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12359-64. Epub 2009 Jul 9. Link to article on publisher's site