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

Virology Journal

Kylene Kehn-Hall³  Yuntao Wu³  Jia Guo³  Kristoffer Valerie¹  Seth M Dever²  Alan Baer³  Beatrix W Meltzer³  Irene Guendel³ 

[1] Department of Radiation Oncology, Virginia Commonwealth University, Richmond 23298, VA, USA;Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond 23298, VA, USA;National Center for Biodefense & Infectious Diseases, School of Systems Biology, George Mason University, Biomedical Research Lab, 10650 Pyramid Place, MS 1J5, Manassas 20110, VA, USA

关键词: Post-translational modification;    Phosphorylation;    ATM;    HIV-1;    BRCA1;    Viral transcription;    Small molecule inhibitor;    Antiviral;   

Others  :  1145089
DOI  :  10.1186/s12985-015-0266-8

 received in 2014-09-25, accepted in 2015-02-14,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Guendel et al.; licensee BioMed Central.

【 图 表 】

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