title: Parvovirus-induced depletion of cyclin B1 prevents mitotic entry of infected cells.
abstract: Parvoviruses halt cell cycle progression following initiation of their replication during S-phase and continue to replicate their genomes for extended periods of time in arrested cells. The parvovirus minute virus of mice (MVM) induces a DNA damage response that is required for viral replication and induction of the S/G2 cell cycle block. However, p21 and Chk1, major effectors typically associated with S-phase and G2-phase cell cycle arrest in response to diverse DNA damage stimuli, are either down-regulated, or inactivated, respectively, during MVM infection. This suggested that parvoviruses can modulate cell cycle progression by another mechanism. In this work we show that the MVM-induced, p21- and Chk1-independent, cell cycle block proceeds via a two-step process unlike that seen in response to other DNA-damaging agents or virus infections. MVM infection induced Chk2 activation early in infection which led to a transient S-phase block associated with proteasome-mediated CDC25A degradation. This step was necessary for efficient viral replication; however, Chk2 activation and CDC25A loss were not sufficient to keep infected cells in the sustained G2-arrested state which characterizes this infection. Rather, although the phosphorylation of CDK1 that normally inhibits entry into mitosis was lost, the MVM induced DDR resulted first in a targeted mis-localization and then significant depletion of cyclin B1, thus directly inhibiting cyclin B1-CDK1 complex function and preventing mitotic entry. MVM infection thus uses a novel strategy to ensure a pseudo S-phase, pre-mitotic, nuclear environment for sustained viral replication.
authors.affiliation: University of Missouri-Columbia, School of Medicine, Columbia, Missouri, United States of America.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Adeyemi
authors.affiliation: University of Missouri-Columbia, School of Medicine, Columbia, Missouri, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pintel
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase; D002460:Cell Line; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D006801:Humans; D051379:Mice; D008915:Minute Virus of Mice / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D010322:Parvoviridae Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism
chemical_list: C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D056744:Cyclin B1; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases