BRCA1 Functions as a Novel Transcriptional Cofactor in HIV-1 Infection




Güendel Sánchez, Irene

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Viruses have naturally evolved elegant strategies to manipulate host 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 the 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 on HIV-1 transcription. Size-exclusion chromatography experiments showed that BRCA1 eluted in the same fraction as other cellular proteins involved in HIV-1 transcription, including Cyclin T1 and Cdk9. BRCA1 was found to be important for viral transcription as cells that lack BRCA1 displayed severely reduced HIV-1 Tat-dependent transcription, and overexpression or selective depletion resulted in enhanced or decreased transcription. Moreover, small molecule inhibition of BRCA1 phosphorylation effector kinases, ATR and ATM, decreased Tat-dependent transcription, whereas a Chk2 inhibitor showed no effect. Furthermore, treatment with curcumin and an ATM inhibitor decreased BRCA1 LTR occupancy. In addition, Tat was found to associate with BRCA1. These results suggest that HIV-1 infection upregulates expression of BRCA1 and may utilize its transcriptional cofactor function for efficient transcription. The presence of BRCA1 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.