Regulation of the transcription cycle contributes to BET bromodomain inhibitor resistance [CUT&RUN]

However, their functions and the consequences of targeting them have not been systematically characterized. Employing complementary interaction-mapping techniques (affinity purification and proximity-dependent biotinylation), we investigate the interactome of 39 BRD-containing proteins together with 110 additional proteins that physically or functionally associate with them.

We uncover 4096 novel interactions, revealing intricate connectivity of the Kac-machinery. We survey interaction landscape rewiring following chemical inhibition for multiple class of BRDs and revealed highly distinctive response following pharmacological intervention between BRD-containing proteins families. Lastly, focusing on the BET protein family, we characterized their interplay with the p38/MAPKAPK2 stress signaling pathway and its contribution to metabolic alterations in the context of metastatic cutaneous melanoma.