Replication of Minute Virus of Mice in Murine Cells Is Facilitated by Virally Induced Depletion of p21

Abstract

TheDNAdamage response to infectionwithminute virus ofmice (MVM) leads to activated p53; however, p21 levels are reduced via a proteasome-mediatedmechanism. This losswas sustained, as virus replicated in infected cells held at theG2/Mborder. Addition of the cyclin-dependent kinase (CDK) inhibitor roscovitine after S-phase entry reducedMVMreplication, suggesting that CDKactivitywas critical for continued viral replication and virus-induced reduction of p21may thus be necessary to prevent inhibition ofCDK. Following infection of a variety of both murine and humancell types, minute virus of mice (MVM) induces a cellular DNA damage response (DDR), which positively contributes to viral replication (3). A number of kinases and effector proteins that are activated and recruited to MVM replication compart-ments, in particular ATM (ataxia-telangiectasia mutated) and members of theMRN (Mre11-Rad50-Nbs1) complex, initiate a signaling cascade that results in activation of a number of cel-lular targets, including Nbs1, Chk2, and p53 (3, 26). p53, a critical node upon which various DNA damage stimuli con-verge (28), was shown to be phosphorylated and stabilized dur-ing MVM infection

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