title: Poly(ADP-ribose) polymerase 1 promotes transcriptional repression of integrated retroviruses.
abstract: Poly(ADP-ribose) polymerase 1 (PARP-1) is a cellular enzyme with a fundamental role in DNA repair and the regulation of chromatin structure, processes involved in the cellular response to retroviral DNA integration. However, the function of PARP-1 in retroviral DNA integration is controversial, probably due to the functional redundancy of the PARP family in mammalian cells. We evaluated the function of PARP-1 in retroviral infection using the chicken B lymphoblastoid cell line DT40. These cells lack significant PARP-1 functional redundancy and efficiently support the postentry early events of the mammalian-retrovirus replication cycle. We observed that DT40 PARP-1(-/-) cells were 9- and 6-fold more susceptible to infection by human immunodeficiency virus type 1 (HIV-1)- and murine leukemia virus (MLV)-derived viral vectors, respectively, than cells expressing PARP-1. Production of avian Rous-associated virus type 1 was also impaired by PARP-1. However, the susceptibilities of these cell lines to infection by the nonretrovirus vesicular stomatitis virus were indistinguishable. Real-time PCR analysis of the HIV-1 life cycle demonstrated that PARP-1 did not impair reverse transcription, nuclear import of the preintegration complex, or viral DNA integration, suggesting that PARP-1 regulates a postintegration step. In support of this hypothesis, pharmacological inhibition of the epigenetic mechanism of transcriptional silencing increased retroviral expression in PARP-1-expressing cells, suppressing the differences observed. Further analysis of the implicated molecular mechanism indicated that PARP-1-mediated retroviral silencing requires the C-terminal region, but not the enzymatic activity, of the protein. In sum, our data indicate a novel role of PARP-1 in the transcriptional repression of integrated retroviruses.
authors.affiliation: Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, USA.
authors.forename: Murilo T D
authors.initials: MT
authors.lastname: Bueno
authors.forename: Daniel
authors.initials: D
authors.lastname: Reyes
authors.forename: Luis
authors.initials: L
authors.lastname: Valdes
authors.forename: Adarsh
authors.initials: A
authors.lastname: Saheba
authors.forename: Eduardo
authors.initials: E
authors.lastname: Urias
authors.forename: Crystal
authors.initials: C
authors.lastname: Mendoza
authors.forename: Oliver I
authors.initials: OI
authors.lastname: Fregoso
authors.forename: Manuel
authors.initials: M
authors.lastname: Llano
mesh_terms: D000818:Animals; D001354:Avian Leukosis Virus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D002460:Cell Line; D002645:Chickens; D015967:Gene Expression Regulation, Viral; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D014158:Transcription, Genetic; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D016662:Virus Integration / Q000235:genetics; D014779:Virus Replication / Q000235:genetics*
chemical_list: C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases