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Abstract
BackgroundViruses 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.MethodsHere 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.ResultsBRCA1 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.ConclusionsBRCA1 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.
Highlights
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
BRCA1 may function as a transcriptional coactivator or corepressor, a function that varies depending on its ability to recruit both the basal transcription machinery and proteins implicated in chromatin remodeling [32,39]
Our data has shown that BRCA1 functions as an enhancer of Human immunodeficiency virus type 1 (HIV-1) transcription through gain-of-function and loss-of-function studies
Summary
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. The breast cancer susceptibility gene, BRCA1, is a tumor suppressor protein that has implications in processes such as cell cycle, DNA repair, and transcription. These functions are accomplished by BRCA1 interacting with cellular transcription and host factors, in addition to stern regulatory mechanisms [15,16]. BRCA1 was first implicated in transcription when its C-terminus [amino acid (aa) 1560–1863] fused to Gal was able to activate transcription [17], with aa1760-1863 being the minimal transactivation domain (TAD) Within this TAD are two BRCA1 C-terminus (BRCT) motifs that are found in a large family of proteins important for DNA damage response, such as DNA ligase IV, p53BP1, and base excision response scaffold protein XRCC1 [18]. It has been further linked to chromatin alterations in cancer, including recruitment to sites of DNA repair, indicating a direct function of BRCA1 in transcriptional control through chromatin structure modulation [33,34,35,36]
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