It is noteworthy that not all APC substrates were subjected to pUL21a-mediated regulation. We did not observe significant difference in Cdc6 or a drastic reduction in thymidine kinase protein levels in the UL21a mutant relative to wild-type viral infection (data not shown). It is possible that these APC substrates are regulated by multiple mechanisms, including APC-independent viral regulation, pUL21a-mediated alteration in APC substrate specificity, and pUL97-mediated phosphorylation of the APC coactivator Cdh1. In fact, Cdh1 from both wild type and UL21a mutant virus infected cells migrated slower in an SDS-PAGE gel compared to that from mock cells, which was previously shown to be due to phosphorylation ( Figure 4E ) [28] . Therefore, virus-induced, Cdh1 phosphorylation-mediated APC regulation appears intact even without pUL21a during HCMV infection.