Multiple roles for Puralpha in cellular and viral regulation

Abstract

Pur-alpha is a ubiquitous multifunctional protein that is strongly conserved throughout evolution, binds to both DNA and RNA and functions in the initiation of DNA replication, control of transcription and mRNA translation. In addition, it binds to several cellular regulatory proteins including the retinoblastoma protein, E2F-1, Sp1, YB-1, cyclin T1/Cdk9 and cyclin A/Cdk2. These observations and functional studies provide evidence that Puralpha is a major player in the regulation of the cell cycle and oncogenic transformation. Puralpha also binds to viral proteins such as the large T-antigen of JC virus (JCV) and the Tat protein of human immunodeficiency virus-1 (HIV-1) and plays a role in the cross-communication of these viruses in the opportunistic polyomavirus JC (JCV) brain infection, progressive multifocal leukoencephalopathy (PML). The creation of transgenic mice with inactivation of the PURA gene that encodes Puralpha has revealed that Puralpha is critical for postnatal brain development and has unraveled an essential role of Puralpha in the transport of specific mRNAs to the dendrites and the establishment of the postsynaptic compartment in the developing neurons. Finally, the availability of cell cultures from the PURA knockout mice has allowed studies that have unraveled a role for Puralpha in DNA repair.

Figure 1

Structure of Purα. A schematic representation of the structure of the Purα protein showing its modular structure is shown. The N-terminus contains a glycine-rich domain that contains a stretch of 18 glycine residues interrupted only by a single serine. The central DNA-binding domain containing 3 class I repeats and 2 class II repeats. The “psycho” domain has homology to polyomavirus large-T antigen from SV40, JCV or BKV and other proteins. Also shown are the C-terminal glutamine-rich and glutamate-rich domains. The regions of Purα that are involved in interacting with other proteins have been experimentally determined in a number of cases: HIV-1 Tat, T-antigen, pRb, Cdk2, E2F-1, YB-1, Cdk9, and Cyclin T1.