The bromodomain inhibitor JQ1 is a molecular glue targeting centromeres

Abstract

Centromeres are the position on each chromosome that orchestrates the accurate partitioning of the genome during cell division. Centromere-dependent cell-cycle checkpoints are maintained by cancer cells to prevent catastrophic chromosome segregation defects in dividing cells1, 2, making centromeric chromatin a valuable target for anti-cancer therapeutics. However, no compounds have been identified that specifically target centromeric chromatin using standard drug discovery approaches. Here we develop a big-data approach to identify the protein composition of repetitive DNA loci, including centromeres, and screen candidate small molecules that act on centromeric chromatin composition. We discover that the BET bromodomain protein BRD4 localises to centromeres and regulates centromeric cohesion. We further show that the bromodomain inhibitor JQ1 affects centromeric BRD4 by stabilising a direct interaction between BRD4 and Centromere Protein B (CENP-B), acting as a molecular-glue that promotes centromere cohesion in a CENP-B-dependent manner. Strikingly, CENP-B transitions from a non-essential protein in JQ1-sensitive cells to the most significant determinant of cell-proliferation in JQ1-resistant cells. Our observations demonstrate a completely overlooked role for BRD4 and JQ1 in directly targeting the centromere, with important consequences for JQ1-derivatives currently entering clinical use3.