Abstract
During lytic infections, HSV-1 genomes are assembled into unstable nucleosomes. The histones required for HSV-1 chromatin assembly, however, are in the cellular chromatin. We have shown that linker (H1) and core (H2B and H4) histones are mobilized during HSV-1 infection, and proposed that the mobilized histones are available for assembly into viral chromatin. However, the actual relevance of histone mobilization remained unknown. We now show that canonical H3.1 and variant H3.3 are also mobilized during HSV-1 infection. Mobilization required no HSV-1 protein expression, although immediate early or early proteins enhanced it. We used the previously known differential association of H3.3 and H3.1 with HSV-1 DNA to test the relevance of histone mobilization. H3.3 binds to HSV-1 genomes first, whereas H3.1 only binds after HSV-1 DNA replication initiates. Consistently, H3.3 and H3.1 were differentially mobilized. H3.1 mobilization decreased with HSV-1 DNA replication, whereas H3.3 mobilization was largely unaffected by it. These results support a model in which previously mobilized H3.1 is immobilized by assembly into viral chromatin during HSV-1 DNA replication, whereas H3.3 is mobilized and assembled into HSV-1 chromatin throughout infection. The differential mobilizations of H3.3 and H3.1 are consistent with their differential assembly into viral chromatin. These data therefore relate nuclear histone dynamics to the composition of viral chromatin and provide the first evidence that histone mobilization relates to viral chromatin assembly.
Highlights
Cellular DNA is wrapped around protein octamers containing two molecules each of histones H2A, H2B, H3, and H4, forming the nucleosome [1]
We have shown that linker (H1) and core (H2B and H4) histones are mobilized during herpes simplex virus 1 (HSV-1) infection, but the significance of this mobilization remained unknown
We find that H3.3 and H3.1 are mobilized during infection
Summary
Cellular DNA is wrapped around protein octamers containing two molecules each of histones H2A, H2B, H3, and H4, forming the nucleosome [1]. Canonical core histone H3.1 differs from the variant histone H3.3 in only four residues These differences suffice to alter nucleosome interactions, such that nucleosomes containing H3.3 are less stable than those containing H3.1 [8]. They dictate specific interactions with histone chaperones, which in turn mediate nucleosome assembly and disassembly. H3.3, which is expressed throughout the cell cycle, interacts with histone chaperone complexes containing histone regulator A (HIRA), hDaxx, or DEK [9,10,11,12]. HIRA mediates the assembly of H3.3 into nucleosomes within the transcription start sites (TSS) of active or repressed genes, and within the coding region of active genes, whereas hDaxx mediates its assembly into telomeric chromatin [13]
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