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The Big BRD Wolf

Brian McWilliams, Ph.D.

In recent years antibodies specifically targeting proteins that contain regions known as bromodomains have become popular among researchers. The bromodomain targets BRD proteins to other proteins known as histones. Histones bind to DNA, acting as a gatekeeper that can allow or prevent other proteins from interacting with DNA. Using their bromodomains, the BRD proteins can activate histone proteins allowing other proteins, such as RNA polymerase, to interact with DNA. Once RNA polymerase interacts and binds to DNA it can perform its function of transcribing RNA.

As research investigating the interplay between BRD and histone proteins has progressed it is apparent that there is a significant relationship between the BRDs and the number of cellular conditions with implications for human health. For example, because of the relationship of BRD to cellular division, it logically follows that aberrant BRD function could result in malignant cell growth and cancer. BRD proteins have been associated with certain types of cancer, such as breast cancer, as a result of their control of the gene encoding cyclin D11. Though it has not been shown conclusively, it has been postulated that inhibition of these BRD proteins may help reduce increased cell division seen in cyclin D1-associated cancers. Furthermore, thymic carcinoma has been observed in a small number of patients whose BRD3 and BRD4 genes are mutated2. In addition, it is thought that inhibition of BRD3 and BRD4 by other cellular proteins may play a role in Burkitt's lymphoma and leukemia3,4.

Despite its importance toward our understanding and treatment of cancer, recent research has focused more on the relationship of BRD proteins to human immunodeficiency virus (HIV)-infected patients. When HIV infects an individual, its DNA is released inside the patient’s cells and integrates itself into the host DNA. This integration allows the virus to avoid the immune response. This avoidance persists until an unknown signal activates HIV from this latent state and new viral particles are made. BRD4 and the HIV protein Tat both interact with regions of DNA associated with HIV replication5. If BRD4 could be inhibited, it may allow for Tat to reactivate viral replication and make elimination of the virus more plausible. Interference with BRD2 has a similar effect as its inhibition can also promote the reactivation of HIV from its latent state6.

As knowledge about the functions of BRD2, BRD3, and BRD4 evolves, the need for tools to study, manipulate, and differentiate these crucial transcription factors will become increasingly significant to both general human health and to understanding the mechanics of cell-cycle control. Bethyl's intent for its validated BRD antibodies is to facilitate further discoveries that advance our understanding of BRD protein function and ultimately improving the lives of patients.

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References

1. Belkina AC, Denis GV. 2012. BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer. June 22;12(7):465-477.

2. Kubonishi I, Takehara N, Iwata J, Sonobe H, Ohtsuki Y, Abe T, Miyoshi I. 1991. Novel t(15;19)(ql5;pl3) Chromosome Abnormality in a Thymic Carcinoma. Cancer Res. Jun 15;51(12):3327-3328.

3. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, Bergeron L, Sims RJ 3rd. 2011. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc. Natl Acad. Sci USA. Oct 4;108(40):16669-16674.

4. Boxer LM, Dang CV. 2001. Translocations involving c‑myc and c‑myc function. Oncogene. Sep 10;20(40):5595-5610.

5. Zhou M, Huang K, Jung K, Cho W, Klase Z, Kashanchi F, Pise-Masison CA, Brady JN. 2009. Bromodomain protein Brd4 regulates human immunodeficiency virus transcription through phosphorylation of CDK9 at threonine 29. J. Virol. Jan;83(2):1036-1044.

6. Boehm D, Calvanese V, Dar RD, Xing S, Schroeder S, Martins L, Aull K, Li PC, Planelles V, Bradner JE, Zhou MM, Siliciano RF, Weinberger L, Verdin E, Ott M. 2013. BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism. Cell Cycle. Feb 1;12(3):452-462.