Poly (ADP-ribose) polymerase-1 silences retroviral expression independently of viral DNA integration or global changes in the abundance of cellular heterochromatin
Poly(ADP-ribose) polymerase-1 (PARP-1) participates in maintenance of the genome integrity by orchestrating DNA repair responses and restricting the expression of foreign genomes. In retroviruses, PARP-1 represses the expression of endogenous and exogenous proviruses in avian cells by a catalytic-independent mechanism that requires the activity of histone deacetylases and DNA methyltransferases. In order to understand better this function of PARP-1, we determined the role of viral DNA integration and organization of the cellular heterochromatin in the retroviral silencing activity of PARP-1. Analysis of infection of PARP-1 knockout and control cells with HIV-1-derived viral vectors harboring a wild type or a catalytically dead integrase mutant indicated that PARP-1 silences unintegrated HIV-1 genomes as efficiently as proviruses, demonstrating that this function of PARP-1 is independent of viral DNA integration. Pharmacological experiments revealed that PARP-1 silences unintegrated HIV-1 by a mechanism that requires the catalytic activity of histone deacetylases but not of PARP-1 or DNA methyltransferases. Although PARP-1 silenced unintegrated HIV-1 genomes through histone deacetylation, PARP-1 did not influence the degree of compaction of the host chromatin as determined by the chromatin accessibility assay to MNase digestion, nor the levels of histone H3 epigenetic marks linked to transcriptional regulation, as evaluated by immunoblot. Therefore, the silencing effect of PARP-1 appears to be retroviral specific rather than a consequence of DNA repair-associated transcriptional repression following viral DNA integration or global changes in the abundance of cellular heterochromatin. In sum, our results add further evidences to a role of PARP-1 in the preservation of the host genome integrity by silencing the expression of invading foreign genomes.
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