Activation of the ATR-mediated DNA damage response by the HIV-1 viral protein R.
DNA damage is a universal inducer of cell cycle arrest at the G2 phase. Infection by the human immunodeficiency virus type 1 (HIV-1) also blocks cellular proliferation at the G2 phase. The HIV-1 accessory gene vpr encodes a conserved 96-amino acid protein (Vpr) that is necessary and sufficient for the HIV-1-induced block of cellular proliferation. In the present study, we examined a recently identified DNA damage-signaling protein, the ATM- and Rad3-related protein, ATR, for its potential role in the induction of G2 arrest by Vpr. We show that inhibition of ATR by pharmacological inhibitors, by expression of the dominant-negative form of ATR, or by RNA interference inhibits Vpr-induced cell cycle arrest. As with DNA damage, activation of ATR by Vpr results in phosphorylation of Chk1. This study provides conclusive evidence of activation of the ATR-initiated DNA damage-signaling pathway by a viral gene product. These observations are important toward understanding how HIV infection promotes cell cycle disruption, cell death, and ultimately, CD4+ lymphocyte depletion.
Department of Microbiology and Immunology, University of Rochester Cancer Center, Rochester, New York 14642, USA.
Mikhail
M
Roshal
Baek
B
Kim
Yonghong
Y
Zhu
Paul
P
Nghiem
Vicente
V
Planelles
D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002110:Caffeine / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division; D002461:Cell Line, Transformed; D002867:Chromones / Q000494:pharmacology; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016195:G2 Phase; D016336:Gene Products, vpr / Q000378:metabolism*; D005799:Genes, Dominant; D005822:Genetic Vectors; D015658:HIV Infections / Q000821:virology; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008156:Luciferases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D054325:vpr Gene Products, Human Immunodeficiency Virus
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D002867:Chromones; D004791:Enzyme Inhibitors; D016336:Gene Products, vpr; D009025:Morpholines; D054325:vpr Gene Products, Human Immunodeficiency Virus; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D002110:Caffeine; D004317:Doxorubicin; D008156:Luciferases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel