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Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains
Lysine acetylation has emerged as a key regulatory modification on histones and other proteins. Histone de-acetylaces (HDACs, the enzymes that remove lysine acetylation (Kac) from histones) are now validated drug targets in cancer, with four FDA approved drugs and several clinical trials seeking to establish higher efficacy and specificity. Kac is recognized by small protein interaction modules called bromodomains (BRDs), leading to the aggregation of complexes involved in transcription and contributing to the control of gene expression (Filippakopoulos et al., 2012; Fujisawa and Filippakopoulos, 2017).
Targeting of bromodomains and disruption of Kac recognition is also emerging as a potential target for therapeutic intervention as it directly blocks assembly and function of the transcriptional machinery, impacting on cell growth and survival (Filippakopoulos et al., 2010; Nicodeme et al., 2010). Indeed, the resulting down-regulation of cell-cycle, growth and pro-survival genes and pathways, leads to cell cycle arrest and apoptosis, identifying targets within this important family that are key drivers of cellular growth (Bradner et al., 2017; Filippakopoulos and Knapp, 2014). However, the precise identity of the complexes assembled by scaffolding members of the BET family, the structural basis of their engagement onto chromatin, their genome-wide distribution, cell-cycle regulation and their rewiring following pharmacological targeting remain largely elusive.
In a collaborative effort to address these questions, the groups of Panagis Filippakopoulos (SGC, Oxford) and Anne-Claude Gingras (Lunenfeld, Toronto) with help from many colleagues across the world have employed interactome mapping methods and biophysical analysis, helping to systematically identify the interaction and proximity partners of human BET proteins. Time course treatments with the pan-BET BRD inhibitor JQ1 revealed broad rewiring of the BET interaction landscape, with three distinct classes of behaviour for the 603 unique interactors identified. The study reports a group of proteins that associate with BET BRDs through canonical and novel Kac-dependent binding modes that dissociate upon inhibitor treatment. It further systematically establishes two classes of extra-terminal (ET)-domain binding motifs that mediate acetylation-independent interactions, offering attractive possibilities for specific therapeutic modulation. Lastly, the study identifies an unexpected increase in several interactions following JQ1 treatment. These increased interactions helped define new negative functions for BRD3 in the regulation of rRNA synthesis and potentially Pol II-dependent gene expression that result in decreased cell proliferation. Taken together, this study outlines the contributions of BET protein modules to their interactomes, allowing for a better understanding of pharmacological rewiring in response to JQ1 (Lambert et al., 2018).
References
- Bradner, J.E., Hnisz, D., and Young, R.A. (2017). Transcriptional Addiction in Cancer. Cell 168, 629-643.
- Filippakopoulos, P., and Knapp, S. (2014). Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 13, 337-356.
- Filippakopoulos, P., Picaud, S., Mangos, M., Keates, T., Lambert, J.P., Barsyte-Lovejoy, D., Felletar, I., Volkmer, R., Muller, S., Pawson, T., Gingras, A.C., Arrowsmith, C.H. & Knapp, S. (2012). Histone recognition and large-scale structural analysis of the human bromodomain family. Cell 149, 214-231.
- Filippakopoulos, P., Qi, J., Picaud, S., Shen, Y., Smith, W.B., Fedorov, O., Morse, E.M., Keates, T., Hickman, T.T., Felletar, I., Philpott, M., Munro, S., McKeown, M.R., Wang, Y., Christie, A.L., West, N., Cameron, M.J., Schwartz, B., Heightman, T.D., La Thangue, N., French, C.A., Wiest, O., Kung, A.L., Knapp, S. & Bradner, J.E. (2010). Selective inhibition of BET bromodomains. Nature 468, 1067-1073.
- Fujisawa, T., and Filippakopoulos, P. (2017). Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat Rev Mol Cell Biol 18, 246-262.
- Lambert, J.-P., Picaud, S., Fujisawa, T., Hou, H., Savitsky, P., Uusküla-Reimand, L., Gupta, G.D., Abdouni, H., Lin, Z.-Y., Tucholska, M., Knight, J.D.R., Gonzalez-Badillo, B., St-Denis, N., Newman, J.A., Stucki, M., Pelletier, L., Bandeira, N., Wilson, M.D., Filippakopoulos, P. & Gingras, A.-C. Interactome rewiring following pharmacological targeting of BET bromodomains (2018) Mol Cell, doi: 10.1016/j.molcel.2018.11.006
- Nicodeme, E., Jeffrey, K.L., Schaefer, U., Beinke, S., Dewell, S., Chung, C.W., Chandwani, R., Marazzi, I., Wilson, P., Coste, H., White, J., Kirilovsky, J., Rice, C.M., Lora, J.M., Prinjha, R.K., Lee, K. & Tarakhovsky. (2010). Suppression of inflammation by a synthetic histone mimic. Nature 468, 1119-1123.