The human immunodeficiency virus type 1 (HIV-1) viral protein R (vpr) gene is an evolutionarily conserved gene among the primate lentiviruses. Several functions are attributed to Vpr including the ability to cause cell death, cell cycle arrest, apoptosis and DNA damage. The Vpr domain responsible for DNA damage as well as the mechanism(s) through which Vpr induces this damage is unknown. Using site-directed mutagenesis, we identified the helical domain II within Vpr (aa 37–50) as the region responsible for causing DNA damage. Interestingly, Vpr Δ(37–50) failed to cause cell cycle arrest or apoptosis, to induce Ku70 or Ku80 and to suppress tumor growth, but maintained its capability to activate the HIV-1 LTR, to localize to the nucleus and to promote nonhomologous end-joining. In addition, our cytogenetic data indicated that helical domain II induced chromosomal aberrations, which mimicked those induced by cisplatin, an anticancer agent. This novel molecular mimicry function of Vpr might lead to its potential therapeutic use as a tumor suppressor.
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We thank past and present members of the Center for Neurovirology and Department of Neuroscience for sharing reagents. This work was supported by grants awarded by NIH to BES and by Susan G Komen Breast Cancer Foundation Research to MFK.
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Siddiqui, K., Del Valle, L., Morellet, N. et al. Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin. Oncogene 27, 32–43 (2008). https://doi.org/10.1038/sj.onc.1210632