Molecular mimicry in inducing DNA damage between HIV-1 Vpr and the anticancer agent, cisplatin.
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 Delta(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.
Siddiqui
K
K
1Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA.
Del Valle
L
L
Morellet
N
N
Cui
J
J
Ghafouri
M
M
Mukerjee
R
R
Urbanska
K
K
Fan
S
S
Pattillo
C B
CB
Deshmane
S L
SL
Kiani
M F
MF
Ansari
R
R
Khalili
K
K
Roques
B P
BP
Reiss
K
K
Bouaziz
S
S
Amini
S
S
Srinivasan
A
A
Sawaya
B E
BE
D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D018716:Molecular Mimicry / Q000187:drug effects / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000502:physiology
D019380:Anti-HIV Agents; D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; D002945:Cisplatin