In this study, we have used immunoprecipitation and mass spectrometry to 
identify over 50 cellular and viral proteins that are associated with the herpes 
simplex virus 1 (HSV-1) ICP8 single-stranded DNA-binding protein. Many of the 
coprecipitating cellular proteins are known members of large cellular complexes 
involved in (i) DNA replication or damage repair, including RPA and MSH6; (ii) 
nonhomologous and homologous recombination, including the catalytic subunit of 
the DNA-dependent protein kinase, Ku86, and Rad50; and (iii) chromatin 
remodeling, including BRG1, BRM, hSNF2H, BAF155, mSin3a, and histone deacetylase 
2. It appears that DNA mediates the association of certain proteins with ICP8, 
while more direct protein-protein interactions mediate the association with 
other proteins. A number of these proteins accumulate in viral replication 
compartments in the infected cell nucleus, indicating that these proteins may 
have a role in viral replication. WRN, which functions in cellular recombination 
pathways via its helicase and exonuclease activities, is not absolutely required 
for viral replication, as viral yields are only very slightly, if at all, 
decreased in WRN-deficient human primary fibroblasts compared to control cells. 
In Ku70-deficient murine embryonic fibroblasts, viral yields are increased by 
almost 50-fold, suggesting that the cellular nonhomologous end-joining pathway 
inhibits HSV replication. We hypothesize that some of the proteins 
coprecipitating with ICP8 are involved in HSV replication and may give new 
insight into viral replication mechanisms.