Transcriptional activation of histone genes requires NPAT-dependent recruitment of TRRAP-Tip60 complex to histone promoters during the G1/S phase transition.
Transcriptional activation of histone subtypes is coordinately regulated and tightly coupled with the onset of DNA replication during S-phase entry. The underlying molecular mechanisms for such coordination and coupling are not well understood. The cyclin E-Cdk2 substrate NPAT has been shown to play an essential role in the transcriptional activation of histone genes at the G(1)/S-phase transition. Here, we show that NPAT interacts with components of the Tip60 histone acetyltransferase complex through a novel amino acid motif, which is functionally conserved in E2F and adenovirus E1A proteins. In addition, we demonstrate that transformation/transactivation domain-associated protein (TRRAP) and Tip60, two components of the Tip60 complex, associate with histone gene promoters at the G(1)/S-phase boundary in an NPAT-dependent manner. In correlation with the association of the TRRAP-Tip60 complex, histone H4 acetylation at histone gene promoters increases at the G(1)/S-phase transition, and this increase involves NPAT function. Suppression of TRRAP or Tip60 expression by RNA interference inhibits histone gene activation. Thus, our data support a model in which NPAT recruits the TRRAP-Tip60 complex to histone gene promoters to coordinate the transcriptional activation of multiple histone genes during the G(1)/S-phase transition.
DeRan
Michael
M
Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Pulvino
Mary
M
Greene
Eriko
E
Su
Chuan
C
Zhao
Jiyong
J
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D017124:Conserved Sequence; D016193:G1 Phase; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016196:S Phase; D016415:Sequence Alignment; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D006657:Histones; C101693:NPAT protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; C113829:transformation-transcription domain-associated protein; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5