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BRCA1 functions as a novel transcriptional cofactor in HIV-1 infection

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dc.contributor.author Guendel, Irene
dc.contributor.author Meltzer, Beatrix W.
dc.contributor.author Baer, Alan
dc.contributor.author Dever, Seth M.
dc.contributor.author Valerie, Kristoffer
dc.contributor.author Guo, Jia
dc.contributor.author Wu, Yuntao
dc.contributor.author Kehn-Hall, Kylene
dc.date.accessioned 2015-09-23T15:44:06Z
dc.date.available 2015-09-23T15:44:06Z
dc.date.issued 2015-03-06
dc.identifier.citation Guendel, Irene, Beatrix W. Meltzer, Alan Baer, Seth M. Dever, Kristoffer Valerie, Jia Guo, Yuntao Wu, and Kylene Kehn-Hall. "BRCA1 functions as a novel transcriptional cofactor in HIV-1 infection." Virology Journal 12, no. 1 (2015): 40. en_US
dc.identifier.uri https://hdl.handle.net/1920/9904
dc.description.abstract Background Viruses have naturally evolved elegant strategies to manipulate the host’s cellular machinery, including ways to hijack cellular DNA repair proteins to aid in their own replication. Retroviruses induce DNA damage through integration of their genome into host DNA. DNA damage signaling proteins including ATR, ATM and BRCA1 contribute to multiple steps in the HIV-1 life cycle, including integration and Vpr-induced G2/M arrest. However, there have been no studies to date regarding the role of BRCA1 in HIV-1 transcription. Methods Here we performed various transcriptional analyses to assess the role of BRCA1 in HIV-1 transcription by overexpression, selective depletion, and treatment with small molecule inhibitors. We examined association of Tat and BRCA1 through in vitro binding assays, as well as BRCA1-LTR association by chromatin immunoprecipitation. Results BRCA1 was found to be important for viral transcription as cells that lack BRCA1 displayed severely reduced HIV-1 Tat-dependent transcription, and gain or loss-of-function studies resulted in enhanced or decreased transcription. Moreover, Tat was detected in complex with BRCA1 aa504-802. Small molecule inhibition of BRCA1 phosphorylation effector kinases, ATR and ATM, decreased Tat-dependent transcription, whereas a Chk2 inhibitor showed no effect. Furthermore, BRCA1 was found at the viral promoter and treatment with curcumin and ATM inhibitors decreased BRCA1 LTR occupancy. Importantly, these findings were validated in a highly relevant model of HIV infection and are indicative of BRCA1 phosphorylation affecting Tat-dependent transcription. Conclusions BRCA1 presence at the HIV-1 promoter highlights a novel function of the multifaceted protein in HIV-1 infection. The BRCA1 pathway or enzymes that phosphorylate BRCA1 could potentially be used as complementary host-based treatment for combined antiretroviral therapy, as there are multiple potent ATM inhibitors in development as chemotherapeutics.
dc.description.sponsorship Publication of this article was funded in part by the George Mason University Libraries Open Access Publishing Fund. en_US
dc.language.iso en_US en_US
dc.publisher BioMed Central en_US
dc.rights Attribution 3.0 United States *
dc.rights.uri http://creativecommons.org/licenses/by/3.0/us/ *
dc.subject antiviral en_US
dc.subject small molecule inhibitor en_US
dc.subject viral transcription en_US
dc.subject BRCA1 en_US
dc.subject HIV-1 en_US
dc.subject ATM en_US
dc.subject phosphorylation en_US
dc.subject post-translational modification en_US
dc.title BRCA1 functions as a novel transcriptional cofactor in HIV-1 infection en_US
dc.type Article en_US
dc.identifier.doi http://dx.doi.org/10.1186/s12985-015-0266-8


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