title: BRCA1 functions as a novel transcriptional cofactor in HIV-1 infection.
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.
authors: National Center for Biodefense & Infectious Diseases, School of Systems Biology, George Mason University, Biomedical Research Lab, 10650 Pyramid Place, MS 1J5, Manassas, VA, 20110, USA. iguendel@gmail.com.
authors: Irene
authors: I
authors: Guendel
authors: National Center for Biodefense & Infectious Diseases, School of Systems Biology, George Mason University, Biomedical Research Lab, 10650 Pyramid Place, MS 1J5, Manassas, VA, 20110, USA. trixmeltzer@gmail.com.
authors: Beatrix W
authors: BW
authors: Meltzer
authors: National Center for Biodefense & Infectious Diseases, School of Systems Biology, George Mason University, Biomedical Research Lab, 10650 Pyramid Place, MS 1J5, Manassas, VA, 20110, USA. abaer5@masonlive.gmu.edu.
authors: Alan
authors: A
authors: Baer
authors: Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, 23298, USA. smdever@vcu.edu.|Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298, USA. smdever@vcu.edu.
authors: Seth M
authors: SM
authors: Dever
authors: Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, 23298, USA. kvalerie@vcu.edu.
authors: Kristoffer
authors: K
authors: Valerie
authors: National Center for Biodefense & Infectious Diseases, School of Systems Biology, George Mason University, Biomedical Research Lab, 10650 Pyramid Place, MS 1J5, Manassas, VA, 20110, USA. jguo3@gmu.edu.
authors: Jia
authors: J
authors: Guo
authors: National Center for Biodefense & Infectious Diseases, School of Systems Biology, George Mason University, Biomedical Research Lab, 10650 Pyramid Place, MS 1J5, Manassas, VA, 20110, USA. ywu8@gmu.edu.
authors: Yuntao
authors: Y
authors: Wu
authors: National Center for Biodefense & Infectious Diseases, School of Systems Biology, George Mason University, Biomedical Research Lab, 10650 Pyramid Place, MS 1J5, Manassas, VA, 20110, USA. kkehnhal@gmu.edu.
authors: Kylene
authors: K
authors: Kehn-Hall
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014158:Transcription, Genetic; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; D054322:tat Gene Products, Human Immunodeficiency Virus