title: 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.
authors.affiliation: Charité Universitätsmedizin Berlin, Labor für Pädiatrische Molekularbiologie, Berlin, Germany.
authors.forename: Henry
authors.initials: H
authors.lastname: Weisbach
authors.affiliation: Charité Universitätsmedizin Berlin, Labor für Pädiatrische Molekularbiologie, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schablowsky
authors.affiliation: Charité Universitätsmedizin Berlin, Labor für Pädiatrische Molekularbiologie, Berlin, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Vetter
authors.affiliation: Charité Universitätsmedizin Berlin, Labor für Pädiatrische Molekularbiologie, Berlin, Germany.
authors.forename: Iris
authors.identifier: 0000-0002-9539-609X
authors.initials: I
authors.lastname: Gruska
authors.affiliation: Charité Universitätsmedizin Berlin, Labor für Pädiatrische Molekularbiologie, Berlin, Germany.
authors.forename: Christian
authors.identifier: 0000-0003-1653-5731
authors.initials: C
authors.lastname: Hagemeier
authors.affiliation: Charité Universitätsmedizin Berlin, Labor für Pädiatrische Molekularbiologie, Berlin, Germany.
authors.forename: Lüder
authors.identifier: 0000-0002-7210-6731
authors.initials: L
authors.lastname: Wiebusch
mesh_terms: D002478:Cells, Cultured; D019925:Cyclin A / Q000235:genetics*; D003587:Cytomegalovirus / Q000378:metabolism / Q000472:pathogenicity*; D003586:Cytomegalovirus Infections / Q000378:metabolism / Q000821:virology*; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D010750:Phosphoproteins / Q000378:metabolism*; D000072020:Synthetic Lethal Mutations / Q000235:genetics*; D014763:Viral Matrix Proteins / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D019925:Cyclin A; D010750:Phosphoproteins; D014763:Viral Matrix Proteins; C056367:pp150 protein, Cytomegalovirus