Abstract
Background The selection of chromosomal targets for retroviral integration varies markedly, tracking with the genus of the retrovirus, suggestive of specific targeting by cellular factors. Gamma-retroviral murine leukemia virus (MLV) DNA integration into the host genome is favored at transcription start sites, but the underlying mechanism for this preference is unknown. The molecular mechanisms of MLV integration are of particular significance due to the fact that MLV-based vectors are used for human gene-therapy. In clinical trials the use of MLV-based vectors to correct primary immunodeficiencies has been curative, but adverse events have occurred that are associated with the insertional activation of proto-oncogenes. Therefore the identification of cellular factors that control MLV integration may provide mechanistic clues to facilitate the development of safer gene-therapy vectors.
Highlights
The selection of chromosomal targets for retroviral integration varies markedly, tracking with the genus of the retrovirus, suggestive of specific targeting by cellular factors
We examined the effects of the purified cellular proteins in in vitro integration assays catalyzed by murine leukemia virus (MLV) integrase
To dissect the role of the cellular proteins in MLV integration site selection, we analyzed the distribution of 11,968 unique integration sites in cells treated with the selective inhibitor JQ-1 or a pool of siRNAs targeting the cellular proteins by 454 pyrosequencing
Summary
The selection of chromosomal targets for retroviral integration varies markedly, tracking with the genus of the retrovirus, suggestive of specific targeting by cellular factors. Gamma-retroviral murine leukemia virus (MLV) DNA integration into the host genome is favored at transcription start sites, but the underlying mechanism for this preference is unknown. The molecular mechanisms of MLV integration are of particular significance due to the fact that MLV-based vectors are used for human gene-therapy. In clinical trials the use of MLV-based vectors to correct primary immunodeficiencies has been curative, but adverse events have occurred that are associated with the insertional activation of proto-oncogenes. The identification of cellular factors that control MLV integration may provide mechanistic clues to facilitate the development of safer gene-therapy vectors
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