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

PLoS Pathogens

David J. Pintel¹  Richard O. Adeyemi¹ 

[1] University of Missouri-Columbia, School of Medicine, Columbia, Missouri, United States of America

关键词: Cyclins;    Phosphorylation;    Viral replication;    Synthesis phase;    Cell cycle;    cell division;    DNA replication;    DNA damage;    Mitosis;   

DOI  :  10.1371/journal.ppat.1003891

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY