
<ArticleTitle>HIV-1 <prot>Vpr</prot> induces cell cycle G2 arrest in fission yeast (Schizosaccharomyces pombe) through a pathway involving regulatory and catalytic subunits of <prot>PP2A</prot> and acting on both <prot>Wee1</prot> and <prot>Cdc25</prot>.</ArticleTitle>
<AbstractText><prot>Viral protein R</prot> (<prot>Vpr</prot>) of human immunodeficiency virus type 1 induces G2 arrest in cells from distantly related eukaryotes including human and fission yeast through inhibitory phosphorylation of tyrosine 15 (Tyr15) on <prot>Cdc2</prot>. Since the DNA damage and DNA replication checkpoints also induce G2 arrest through phosphorylation of Tyr15, it seemed possible that <prot>Vpr</prot> induces G2 arrest through the checkpoint pathways. However, <prot>Vpr</prot> does not use either the early or the late checkpoint genes that are required for G2 arrest in response to DNA damage or inhibition of DNA synthesis indicating that <prot>Vpr</prot> induces G2 arrest by an alternative pathway. It was found that <prot>protein phosphatase 2A</prot> (<prot>PP2A</prot>) plays an important role in the induction of G2 arrest by <prot>Vpr</prot> since mutations in genes coding for a regulatory or catalytic subunit of <prot>PP2A</prot> reduce <prot>Vpr</prot>-induced G2 arrest. <prot>Vpr</prot> was also found to upregulate <prot>PP2A</prot>, supporting a model in which <prot>Vpr</prot> activates the <prot>PP2A</prot> holoenzyme to induce G2 arrest. <prot>PP2A</prot> is known to interact genetically in fission yeast with the <prot>Wee1</prot> kinase and <prot>Cdc25</prot> phosphatase that act on Tyr15 of <prot>Cdc2</prot>. Both <prot>Wee1</prot> and <prot>Cdc25</prot> play a role in <prot>Vpr</prot>-induced G2 arrest since a <prot>wee1</prot> deletion reduces <prot>Vpr</prot>-induced G2 arrest and a direct in vivo assay shows that Vpr inhibits <prot>Cdc25</prot>. Additional support for both <prot>Wee1</prot> and <prot>Cdc25</prot> playing a role in <prot>Vpr</prot>-induced G2 arrest comes from a genetic screen, which identified genes whose overexpression affects <prot>Vpr</prot>-induced G2 arrest. For this genetic screen, a strain was constructed in which cell killing by <prot>Vpr</prot> was nearly eliminated while the effect of <prot>Vpr</prot> on the cell cycle was clearly indicated by an increase in cell length. Overexpression of the <prot>wos2</prot> gene, an inhibitor of <prot>Wee1</prot>, suppresses <prot>Vpr</prot>-induced G2 arrest while overexpression of <prot>rad25</prot>, an inhibitor of <prot>Cdc25</prot>, enhances <prot>Vpr</prot>-induced G2 arrest. These two genes may be part of the uncharacterized pathway for <prot>Vpr</prot>-induced G2 arrest in which <prot>Vpr</prot> upregulates <prot>PP2A</prot> to activate <prot>Wee1</prot> and inhibit <prot>Cdc25</prot>.</AbstractText>
