HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination - PubMed (original) (raw)
. 2007 Jan 25;26(4):477-86.
doi: 10.1038/sj.onc.1209831. Epub 2006 Sep 18.
M Shimura, M Kinomoto, Y Takizawa, K Tokunaga, T Taguchi, S Hoshino, K Miyagawa, T Sata, H Kurumizaka, A Yuo, Y Ishizaka
Affiliations
- PMID: 16983346
- DOI: 10.1038/sj.onc.1209831
HIV-1 Vpr induces ATM-dependent cellular signal with enhanced homologous recombination
C Nakai-Murakami et al. Oncogene. 2007.
Abstract
An ATM-dependent cellular signal, a DNA-damage response, has been shown to be involved during infection of human immunodeficiency virus type-1 (HIV-1), and a high incidence of malignant tumor development has been observed in HIV-1-positive patients. Vpr, an accessory gene product of HIV-1, delays the progression of the cell cycle at the G2/M phase, and ATR-Chk1-Wee-1, another DNA-damage signal, is a proposed cellular pathway responsible for the Vpr-induced cell cycle arrest. In this study, we present evidence that Vpr also activates ATM, and induces expression of gamma-H2AX and phosphorylation of Chk2. Strikingly, Vpr was found to stimulate the focus formation of Rad51 and BRCA1, which are involved in repair of DNA double-strand breaks (DSBs) by homologous recombination (HR), and biochemical analysis revealed that Vpr dissociates the interaction of p53 and Rad51 in the chromatin fraction, as observed under irradiation-induced DSBs. Vpr was consistently found to increase the rate of HR in the locus of I-SceI, a rare cutting-enzyme site that had been introduced into the genome. An increase of the HR rate enhanced by Vpr was attenuated by an ATM inhibitor, KU55933, suggesting that Vpr-induced DSBs activate ATM-dependent cellular signal that enhances the intracellular recombination potential. In context with a recent report that KU55933 attenuated the integration of HIV-1 into host genomes, we discuss the possible role of Vpr-induced DSBs in viral integration and also in HIV-1 associated malignancy.
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