Abstract
The genomes of DNA tumor viruses regain nuclear localization after nuclear envelope breakdown during mitosis through the action of a viral protein with a chromatin-tethering domain (CTD). Here, we report that the human cytomegalovirus (HCMV) genome is maintained during mitosis by the CTD of the viral IE19 protein. Deletion of the IE19 CTD or disruption of the IE19 splice acceptor site reduced viral genome maintenance and progeny virion formation during infection of dividing fibroblasts, both of which were rescued by IE19 ectopic expression. The discovery of a viral genome maintenance factor during productive infection provides new insight into the mode of HCMV infection implicated in birth defects, organ transplant failure, and cancer.IMPORTANCE Human cytomegalovirus (HCMV) is the leading infectious cause of birth defects, represents a serious complication for immunocompromised HIV/AIDS and organ transplant patients, and contributes to both immunosenescence and cardiovascular diseases. HCMV is also implicated in cancers such as glioblastoma multiforme (GBM) and infects ex vivo-cultured GBM tumor cells. In dividing tumor cells, the genomes of DNA tumor viruses regain nuclear localization after nuclear envelope breakdown during mitosis. This mitotic survival is mediated by a viral protein with a chromatin-tethering domain (CTD). Here, we report that the HCMV genome is maintained in dividing fibroblasts by the CTD of the viral IE19 protein. The discovery of a viral genome maintenance factor during productive infection could help explain viral genome dynamics within HCMV-positive tumors as well as during latency.
Highlights
The genomes of DNA tumor viruses regain nuclear localization after nuclear envelope breakdown during mitosis through the action of a viral protein with a chromatin-tethering domain (CTD)
We show that the CTD, in the context of an alternatively spliced UL123 transcript encoding a monomeric protein isoform designated IE19, helps the viral genome to survive mitosis so that the viral genome can initiate the cascade of productive-phase gene expression in daughter cells entering G1 phase after completing mitosis
We confirmed previous reports that G0/G1 fibroblasts infected with Human cytomegalovirus (HCMV) initiate immediate early (IE) gene expression quickly, while S-phase-infected fibroblasts initiate IE gene expression only after a pronounced delay [12]
Summary
The genomes of DNA tumor viruses regain nuclear localization after nuclear envelope breakdown during mitosis through the action of a viral protein with a chromatin-tethering domain (CTD). The genomes of DNA tumor viruses regain nuclear localization after nuclear envelope breakdown during mitosis. This mitotic survival is mediated by a viral protein with a chromatin-tethering domain (CTD). Human cytomegalovirus (HCMV) infection of primary human fibroblasts in the G0 or G1 phase drives them to the G1/S border but prevents them from progressing through the S phase [2,3,4,5,6,7] Under these conditions, productive infection initiates immediately and is highly efficient. HCMV devotes multiple mechanisms to synchronization of infected cells in favorable cell cycle phases while preventing cells that are actively replicating virus from entering mitosis, where mitotic catastrophes limit productive replication [14, 15]
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