Parvovirus-Induced Depletion of Cyclin B1 Prevents Mitotic Entry of Infected Cells

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. © 2014 adeyemi,pintel.