Interactome rewiring following pharmacological targeting of BET bromodomains
Lamber J-P., PICAUD S., Fujisawa T., Hou H., SAVITSKY P., Uusküla-Reimand L., Gupta G., Abdouni H., Lin Z-Y., Tucholska M., Knight JDR., Gonzalez-Badillo B., St-Denis N., NEWMAN JA., Stucki M., Pelletier L., Bandeira N., Wilson MD., FILIPPAKOPOULOS P., Gingras A-C.
Targeting bromodomains (BRDs) of the bromo-and-extra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, BRD3, BRD4 and BRDT following treatment with the pan-BET BRD inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behaviour for the 603 unique interactors identified. A group of proteins associate in a JQ1-sensitive manner with BET BRDs through canonical and new binding modes, while two classes of extra-terminal (ET)-domain binding motifs mediate acetylation-independent interactions. Lastly, we identify an unexpected increase in several interactions following JQ1 treatment that define negative functions for BRD3 in the regulation of rRNA synthesis and potentially RNAPII-dependent gene expression that result in decreased cell proliferation. Together, our data highlight the contributions of BET protein modules to their interactomes allowing for a better understanding of pharmacological rewiring in response to JQ1