Circadian CLOCK histone acetyl transferase localizes at ND10 nuclear bodies and enables herpes simplex virus gene expression.
Expression of herpes simplex virus genes at the initiation of replication involves two steps that take place at ND10 nuclear bodies. These are suppression of cellular repressors that attempt to silence viral DNA and remodeling of the viral chromatin to make it accessible for transcription. In earlier studies we reported on the mechanism by which viral proteins ICP0 and U(S)3 protein kinase modify and disrupt the HDAC1/CoREST/REST/LSD1 repressor complex. The remodeling step requires in addition acetylation of histones bound to DNA. In an attempt to identify the enzyme, we took note of the observation that ICP0 physically and functionally interacts with Bmal1, a partner of the CLOCK histone acetyl transferase, and key members of the bHLH-PAS family of transcriptional factors. The Bmal11 and CLOCK heterodimer is best known as a regulator of the circadian oscillation in the mammalian CLOCK system. In this article we report the following: (i) in infected cells both Bmal1 and CLOCK localize at ND10 bodies; (ii) wild-type virus stabilizes the CLOCK protein; (iii) overexpression of CLOCK partially compensates for the absence of ICP0 and enables higher yields in cells infected with a ΔICP0 mutant and this activity is not expressed by CLOCK mutants lacking histone acetyl transferase activity; and (iv) depletion of CLOCK in cells infected with wild-type virus results in significant decrease in the expression of all viral proteins tested. We conclude that ICP0 interacts with Bmal1 and by extension with CLOCK histone acetyl transferase to remodel viral chromatin.
Kalamvoki
Maria
M
Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, Chicago, IL 60637, USA.
Roizman
Bernard
B
D056930:ARNTL Transcription Factors / Q000378:metabolism; D000818:Animals; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D042002:Chromatin Assembly and Disassembly / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D015967:Gene Expression Regulation, Viral / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000378:metabolism*; D034622:RNA Interference; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014709:Vero Cells; D016662:Virus Integration / Q000502:physiology*
D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C094297:CALCOCO2 protein, human; D017931:DNA Primers; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D056926:CLOCK Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1