Human cytomegalovirus prevents replication licensing by inhibiting MCM loading onto chromatin.

To allow DNA replication only once per cell cycle, origins of replication are reactivated ('licensed') during each G1 phase. Licensing is facilitated by assembly of the pre-replicative complex (pre-RC) at origins that concludes with loading the mini-chromosome maintenance (MCM) complex onto chromatin. Here we show that a virus exploits pre-RC assembly to selectively inhibit cellular DNA replication. Infection of quiescent primary fibroblasts with human cytomegalovirus (HCMV) induces all pre-RC factors. Although this is sufficient to assemble the MCM-loading factors onto chromatin, as it is in serum-stimulated cells, the virus inhibits loading of the MCM complex itself, thereby prematurely abrogating replication licensing. This provides a new level of control in pre-RC assembly and a mechanistic rationale for the unusual HCMV-induced G1 arrest that occurs despite the activation of the cyclin E-dependent transcription programme. Thus, this particularly large virus might thereby secure the supply with essential replication factors but omit competitive cellular DNA replication.