Synthetic lethal mutations in the cyclin A interface of human cytomegalovirus
- PMID: 28129404
- PMCID: PMC5298330
- DOI: 10.1371/journal.ppat.1006193
Synthetic lethal mutations in the cyclin A interface of human cytomegalovirus
Abstract
Generally, the antagonism between host restriction factors and viral countermeasures decides on cellular permissiveness or resistance to virus infection. Human cytomegalovirus (HCMV) has evolved an additional level of self-imposed restriction by the viral tegument protein pp150. Depending on a cyclin A-binding motif, pp150 prevents the onset of viral gene expression in the S/G2 cell cycle phase of otherwise fully permissive cells. Here we address the physiological relevance of this restriction during productive HCMV infection by employing a cyclin A-binding deficient pp150 mutant virus. One consequence of unrestricted viral gene expression in S/G2 was the induction of a G2/M arrest. G2-arrested but not mitotic cells supported viral replication. Cyclin A destabilization by the viral gene product pUL21a was required to maintain the virus-permissive G2-arrest. An HCMV double-point mutant where both pp150 and pUL21a are disabled in cyclin A interaction forced mitotic entry of the majority of infected cells, with a severe negative impact on cell viability and virus growth. Thus, pp150 and pUL21a functionally cooperate, together building a cell cycle synchronization strategy of cyclin A targeting and avoidance that is essential for productive HCMV infection.
Conflict of interest statement
The authors have declared that no competing interests exist.
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References
-
- Morgan DO. The Cell Cycle: Principles of Control. London: New Science Press; 2007.
-
- Mittnacht S, Boshoff C. Viral cyclins. Rev Med Virol. 2000;10: 175–184. - PubMed
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