HiNF-P directly links the cyclin E/CDK2/p220NPAT pathway to histone H4 gene regulation at the G1/S phase cell cycle transition.
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.
Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
Angela
A
Miele
Corey D
CD
Braastad
William F
WF
Holmes
Partha
P
Mitra
Ricardo
R
Medina
Ronglin
R
Xie
Sayyed K
SK
Zaidi
Xin
X
Ye
Yue
Y
Wei
J Wade
JW
Harper
Andre J
AJ
van Wijnen
Janet L
JL
Stein
Gary S
GS
Stein
D020816:Amino Acid Motifs; D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D016193:G1 Phase / Q000235:genetics; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D025941:Protein Interaction Mapping; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism*; D016196:S Phase / Q000235:genetics*; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D018797:Cell Cycle Proteins; D002843:Chromatin; D019927:Cyclin E; C442219:HINFP protein, human; D006657:Histones; C101693:NPAT protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2